CN1509275A - Metalloproteinase inhibitors - Google Patents

Metalloproteinase inhibitors Download PDF

Info

Publication number
CN1509275A
CN1509275A CNA028100417A CN02810041A CN1509275A CN 1509275 A CN1509275 A CN 1509275A CN A028100417 A CNA028100417 A CN A028100417A CN 02810041 A CN02810041 A CN 02810041A CN 1509275 A CN1509275 A CN 1509275A
Authority
CN
China
Prior art keywords
alkyl
group
apci
methyl
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CNA028100417A
Other languages
Chinese (zh)
Inventor
�������ɭ
安德斯·埃里克森
�����Ƥ��
马蒂·莱皮斯托
���¿˻�ά��
迈克尔·伦德克维斯特
˹��â�˰�����ɭФ����
马格努斯·芒克阿弗罗森肖尔德
帕沃尔·兹拉托伊德斯基
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from SE0100902A external-priority patent/SE0100902D0/en
Priority claimed from SE0100903A external-priority patent/SE0100903D0/en
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of CN1509275A publication Critical patent/CN1509275A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
    • C07D233/78—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pulmonology (AREA)
  • Dermatology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Urology & Nephrology (AREA)
  • Hospice & Palliative Care (AREA)
  • Oncology (AREA)
  • Psychiatry (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Ophthalmology & Optometry (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Abstract

The invention provides a metalloproteinsae inhibitor compound comprising a metal binding group having formula (I), for use in the treatment of a disease or condition mediated by one or more metalloproteinase enzymes wherein X is selected from NR1, O, S; B is C or CH, Y1 and Y2 are idenpendently selected from O, S; R1 is selected from H, alkyl, haloalkyl.

Description

Inhibitors of metalloproteinase
The present invention relates to use the compound that suppresses metalloprotease and be particularly related to the pharmaceutical composition of use as therapeutical agent.
Compound of the present invention is the inhibitor of one or more metalloproteases.Metalloprotease belongs to proteolytic enzyme (enzyme) superfamily, and its member significantly increases in recent years.Based on the consideration of 26S Proteasome Structure and Function, be that N.M.Hooper is at (1994) FEBS Letters with these enzyme classifications 354: family described in the 1-6 and subtribe.The example of metalloprotease comprises: matrix metalloproteinase (MMPs), such as collagenase (MMP1, MMP8, MMP13), gelatinase (MMP2, MMP9), stromelysin (MMP3, MMP10, MMP11), matrilysin (MMP7), metalloelastase (MMP12), enamelysin (MMP19), MT-MMPs (MMP14, MMP15, MMP16, MMP17); The reprolysin or adamalysin or MDC family comprise secretases and sheddases, such as TNF saccharase (ADAM10 and TACE); Astacin family comprises such as precollagen processing protease (PCP); With other metalloprotease, such as aggrecanase, endothelin-converting enzyme family and angiotensin converting enzyme family.
Think that metalloprotease is important in the plethora that comprises the physiological lysis of rebuilding such tissue reconstruction in the menstrual period such as fetal development, bone forming and uterus.This viewpoint is based on the ability of the so wide scope matrix substrate of metalloprotein enzymatic lysis such as collagen protein, proteoglycan and fibronectin.Think that also metalloprotease is being that important (more complete content is referring to N.M.Hooper etc., (1997) Biochem J. in such biological important membrane proteic posttranslational protein hydrolysis processing or the dispose procedure such as the processing of the so biological important cells amboceptor of tumour necrosis factor (TNF) or secretion with such as low affinity IgE acceptor CD23 321: 265-279).
Metalloprotease is relevant with numerous disease or illness.Suppress one or more MMP activities and can fully advantageously treat following these diseases or illness, for example: various inflammation and anaphylactic disease, such as sacroiliitis (especially rheumatoid arthritis, osteoarthritis and gout), gastrointestinal tract inflammation (especially enteritis disease, ulcerative colitis and gastritis), skin inflammation (especially psoriatic, eczema, dermatitis); Metastases or infringement; With the relevant disease of the uncontrollable degraded of extracellular matrix, such as osteoarthritis; Bone resorption disease (such as osteoporosis and Paget's disease); Relevant disease takes place with abnormal vascular; The strengthened collagen relevant with skin wound healing with diabetes, periodontopathy (such as oulitis), keratohelcosis, skin ulcer, postoperative illness (such as colocolic anastomosis) rebuild; Maincenter and peripheral nervous system demyelination (such as multiple sclerosis); Alzheimer's disease; Observed extracellular matrix is rebuild in the cardiovascular disorder such such as restenosis and atherosclerosis; Asthma; Rhinitis; And chronic obstructive pulmonary disease (COPD).
The MMP12 that is also referred to as scavenger cell elastoser or metalloelastase at first by Shapiro etc. (1992, Journal of Biological Chemistry 267: 4664) at the mouse vivo clone and still clone in human body in nineteen ninety-five by them.Preferably in activated macrophage, express MMP-12 and verified their secretions from the beginning from smoker's pulmonary alveolar macrophage (Shapiro etc., 1993, Journal ofBiological Chemistry, 268: 23824) and the foam cell in the atherosclerotic lesions (Matsumoto etc., 1998, Am J Pathol 153: 109).The COPD mouse model based on cigarette with mouse attack 6 months, wherein weekly 6 days, every day 2 cigarettes.Carrying out this processing back wild-type mice generation pulmonary emphysema.When test MMP12 rejected mouse in this model, tangible pulmonary emphysema did not take place in them, and this result proves that forcefully MMP-12 is the key enzyme in the COPD pathogenesis.At 1999 of Anderson and Shinagawa, Current Opinion in Anti-inflammatory andImmunomodulatory Investigational Drugs 1 (1): inquired into the such effect of MMPs in COPD (pulmonary emphysema and bronchitis) among the 29-38 such as MMP12.Recently find that smoking increases scavenger cell deutero-MMP-12 expression among macrophages infiltration and the people's carotid artery spot Kangavari.(Matetzky S, Fishbein MC etc., Circulation 102:(18), 36-39 Suppl.S, Oct 31,2000).
MMP13 or collagenase 3 initial clones are from cDNA library [J.M.P.Freije etc. (1994) the Joumal of Biological Chemistry that derives from breast tumor 269 (24): 16766-16773].PCR-RNA analysis revealed MMP13 from the RNAs of extensive tissue expressed be limited to mammary cancer, and in mammary gland fibroadenoma, normal or tranquillization mammary gland, placenta, liver, ovary, uterus, prostate gland or the parotid gland or breast cancer cell line (T47-D, MCF-7 and ZR75-1), do not find this situation.The epidermal keratinocyte [N.Johansson etc., (1997) the Cell Growth Differ. that after this observations, are transforming 8 (2): 243-250], squamous cell carcinoma [N.Johansson etc., (1997) Am.J.Pathol. 151 (2): 499-508] and epidermis tumour [K.Airola etc., (1997) J.Invest.Dermatol. 109 (2): 225-231] in detected MMP13.These results suggest MMP13 by the epithelium skin cell secretion that transforms and they can participate in the extracellular matrix degraded with especially as the relevant cell-matrix interaction of observed transfer in the Evil epithelial growth Zhong mammary cancer infringement and skin carcinoma generation.
Recently the data suggest MMP13 that announces works in other reticular tissue upgrades.For example, because with MMP13 ' substrate specificity with to the degraded preferential selectivity of II collagen type consistent [P.G.Mitchell etc., (1996) J.Clin.Invest. 97 (3): 761-768; V.Knauper etc., (1996) TheBiochemical Journal 271: 1544-1550], so infer MMP13 [M.Stahle-Backdahl etc., (1997) Lab.Invest. in elementary ossified and bone process of reconstruction 76 (5): 717-728; N.Johansson etc., (1997) Dev.Dyn. 208 (3): 387-397], in the damaging joint disease process such such as similar rheumatism and osteoarthritis [D.Wernicke etc., (1996) J.Rheumatol. 23: 590-595; P.G.Mitchell etc., (1996) J.Clin.Invest. 97 (3): 761-768; O.Lindy etc., (1997) Arthritis Rheum 40 (8): 1391-1399] and in the aseptic relaxation of hip replacement [S.Imai etc., (1998) J.Bone Joint Surg.Br. 80 (4): 701-710] work.If MMP13 is positioned at the gingival tissues epithelium of people's chronic inflammatory diseases mucous membrane, its also relevant [V.J.Uitto etc., (1998) Am.J.Pathol. so with grownup's chronic periodontitis 152 (6): 1489-1499] and the collagen stroma that participates in the chronic trauma rebuild [M.Vaalamo etc., (1997) J.Invest.Dermatol. 109 (1): 96-101].
MMP9 (collagenase B; 92kDa IV Collagen Type VI enzyme; The 92kDa collagenase) be at first in purifying in 1989, secretory protein [S.M.Wilhelm etc. (1989) the J.Biol Chem. that clones and check order then 264 (29): 17213-17221; J.Biol Chem. (1990) 265 (36): the errata of announcing in 22570].Recently the summary to MMP9 provides splendid source: T.H.Vu﹠amp for specifying information and reference about this proteolytic enzyme; Z.Werb (1998) (: among the Matrix Metalloproteinases, 1998. by W.C.Parks﹠amp; R.P.Mecham edits .pp115-148.Academic?Press.ISBN0-12-545090-7)。From T.H.Vu﹠amp; Viewpoint below having extracted in the summary of Z.Werb (1998).
The expression of MMP9 is generally limited to several cell types, comprises trophoderm, osteoclast, neutrophil(e) cell and scavenger cell.Yet, can in these cell and other cell type, induce its expression by several amboceptors, comprise making cells contacting somatomedin or cytokine.They are the identical amboceptors of being correlated with the reaction that causes inflammation usually.As other secretion MMPs that uses, MMP9 is released as the proenzyme of inactivation, and it is cracked into the enzyme with enzymic activity subsequently.Still do not understand being used for activating required proteolytic enzyme in this body.By the balance of further regulating active MMP9 and fermentoid in vivo with the interaction of the protein TIMP-1 (tissue depressant of metalloprotease-1) of natural appearance.TIMP-1 is in conjunction with the C-end region of MMP9, thereby causes the inhibition to the catalyst structure domain of MMP9.Before the MMP9 inductive is expressed, preceding-MMP9 is cracked into the TIMP-1 of active MMP9 and existence balance unite the amount of having determined the catalytic activity MMP9 that exists on the localized site.Proteolytic activity MMP9 attacks the substrate that comprises gelatin, elastin and natural IV type and collagen type v albumen; It does not have activity to natural type i collagen albumen, proteoglycan or ln.
There has been mass data to point out the effect of MMP9 in various physiology and pathologic process.Physiological action comprises by uterine epithelium infringement embryo trophoderm in the embryo transfer commitment, migrates into tissue in osteogenesis and developmental some effect with from the inflammatory cell of vascular system.
Use MMP-9 burst size that enzyme immunoassay measures from the liquid of not treating asthma and AM supernatant liquor with from other colony liquid compare remarkable increase [Am.J.Resp.Cell﹠amp with the AM supernatant liquor; Mol.Biol., (Nov 1997) 17 (5):583-591].In addition, in some other pathologic condition, observed the MMP9 that increases and expressed, hinted thus in lysis, such as COPD, sacroiliitis, metastases, alzheimer's disease, multiple sclerosis with cause having MMP9 in the plaque rupture in the atherosclerosis of the acute coronary such such as myocardial infarction.
MMP-8 (collagenase-2, neutrophil's collagenase) is 53 kD enzymes in the matrix metalloproteinase family of preferentially expressing in the neutrophil(e) cell.Recent research show MMP-8 also at other cell, express in such as the osteoarthritis chondrocyte [Shlopov etc., (1997) Arthritis Rheum, 40: 2065].The MMPs that is produced by the neutrophil(e) cell can cause tissue reconstruction, should have positive effect in for example pulmonary fibrosis disease and the degenerative disorders as pulmonary emphysema and block MMP-8 thus.Find that also MMP-8 can be subjected to incremental adjustments in osteoarthritis, thereby show that blocking-up MMP-8 can also help treating this disease.
MMP-3 (stromelysin-1) is the 53kD enzyme in the matrix metalloproteinase family.Separate in the inoblast of inflammation gum, confirmed the MMP-3 activity [Uitto V.J. etc., (1981) J.PeriodontalRes., 16: 417-424] and the level of enzyme relevant with the severity of gingival disease [Overall C.M. etc., (1987) J.Periodontal Res., 22: 81-88].MMP-3 also by the substrate keratinocyte in various some ulcer produce [Saarialho-Kere U.K. etc., (1994) J.Clin.Invest., 94: 79-88].To substrate keratinocyte, MMP-3mRNA and protein have been detected contiguous away from the edge of wound that may represent hyperplasia epidermis position.MMP-3 can stop the epidermis healing thus.Several researchists confirmed MMP-3 in from rheumatoid and osteoarthritis patient's synovia, compare and continue to raise with control group [Walakovits L.A. etc., (1992) Arthritis Rheum., 35: 35-42; Zafarullah M. etc., (1993) J.Rheumatol., 20: 693-697].These researchs provide the foundation for the viewpoint of MMP-3 inhibitor for treating disease, and the disease of being treated comprises because of lymphocytic infiltration and causes the extracellular matrix of inflammation to break or organ dysfunction is sayed that essential structural integrity loses.
Known many inhibitors of metalloproteinase (for example, referring to Beckett R.P. and Whittaker M. 1998, Exp.Opin.Ther.Patents, 8 (3): among the 259-282 to the summary of MMP inhibitor).The inhomogeneity compound can have in various degree effect and selectivity to suppressing different metal proteolytic enzyme.
Whittaker M. etc. (1999, Chemical Reviews 99(9): 2735-2776) summarized extensive known MMP inhibitor compound.They think that effective MMP inhibitor needs zinc binding moiety or ZBG (can sequestering activity position zinc (II) ionic functional group), at least a providing with the enzyme main chain functional group of interactional hydrogen bond taken place and carried out with the enzyme sublocus the interactional one or more side chains of effective Van der Waals taking place.Zinc binding moiety on the known MMP inhibitor comprises carboxylic moiety, hydroxamic acid part, sulfhedryl or sulfydryl etc.For example, Whittaker M. etc. has inquired into following MMP inhibitor:
Above-claimed cpd has entered the clinical development stage.It has sulfydryl acyl group zinc binding moiety, is positioned at trimethylammonium glycolylurea base ethyl and leucyl-tertiary butyl glycyl main chain on the P1 position.
Figure A0281004100112
Above-claimed cpd has sulfydryl acyl group zinc binding moiety and imide part on the P1 position.
Figure A0281004100113
The exploitation above-claimed cpd is used for the treatment of sacroiliitis.It has the succinyl-hydroxamic acid zinc binding moiety and the trimethylammonium glycolylurea base ethyl of non-peptide on the P1 position.
Above-claimed cpd is the phthalimido derivative that suppresses collagenase.It has the succinyl-hydroxamic acid zinc binding moiety ring imide part of non-peptide on P1.Whittaker M. etc. has also inquired into other MMP inhibitor that has P1 cyclo-imino and various zinc binding moiety (succinyl-hydroxamate, carboxylic acid, thiol, contain phosphorous group).
Figure A0281004100122
Above-claimed cpd look like MMP8 and MMP9 good inhibitor (PCT patent application WO9858925, WO9858915).They have pyrimidine-2,3,4-triketone zinc binding moiety.
Following compounds is unknown as the MMP inhibitor :-
Lora-Tamayo, and M etc. (1968, An.Quim 64 (6): 591-606) synthetic method as the following compounds of potential anticarcinogen has been described:
Figure A0281004100131
The synthetic method and the anti-convulsant activity of following compounds have been described in the Czech patents 151744 (19731119) and 152617 (1974022):
Figure A0281004100132
R＝4-NO2，4-OMe，2-NO2，
Following compounds as intermediate has been described in the U.S. Pat 3529019 (19700915):
Figure A0281004100133
Describe the compound that is used for the treatment of visual disorder among the PCT patent application WO 00/09103, comprised following compounds (compound 81 and 83, Table A, 47 pages):
Figure A0281004100134
Japanese Patent 5097814 (1993) has been introduced a kind of method for preparing as the compound of producing antibiotic intermediate, comprises the compound of following formula:
Figure A0281004100141
People such as Morton (1993, J Agric Food Chem 41 (1): 148-152) introduced a kind of preparation of the compound with Fungicidally active of the compound that comprises following formula:
Figure A0281004100142
Dalgatov, people such as D (1967, Khim.Geterotsikl.Soedin.5:908-909) introduced synthetic following formula: compound, do not use this compound but introduce:
Crooks, and people such as P (1989, J.Heterocyclic Chem. 26 (4): 1113-17) introduced synthetic following formula: compound, this compound has been tested the anti-convulsant activity of rat:
Gramain, people such as J.C (1990) Recl.Trav.Chim.Pays-Bas 109: 325-331) introduced synthetic following formula: compound:
Synthetic method to important amino acid has been described among the Japanese Patent No. JP 63079879 (1988) in the intermediate way.Following compounds is used as raw material:
Figure A0281004100152
Wolfe, and J etc. (1971, Synthesis 6: 310-311) describe the synthetic method of following compounds, but do not pointed out this application of compound:
Figure A0281004100153
Moharram etc. (1983, Egypt J.Chem. 26: 301-11) following compounds has been described:
The synthetic method of following compounds has been described and as the application of foodstuff additive in the hungarian patent numbers 26403 (1983):
Figure A0281004100155
We have had been found that new that play the inhibitors of metalloproteinase effect and can be used as treatment reagent, be used for the compound of the method for human or animal body now.Especially, we find, and these compounds are effective MMP inhibitor and have required field of activity, useful effect, selectivity and/or medicine dynamic performance.These compounds are to have undiscovered melts combine base in the known metal proteinase inhibitor.
First aspect present invention is provided for treating hydrolyzable ester in the inhibitors of metalloproteinase compound of the disease that mediated by one or more metalloproteases or illness or acceptable salt of its medicine or the body, wherein this inhibitors of metalloproteinase compound comprises melts combine group and one or more other functional group or side chain, it is characterized in that the melts combine base has following general formula (I)
Figure A0281004100161
Wherein X is selected from NR1, O, S;
Y1 and Y2 are independently selected from O, S;
R1 is selected from H, alkyl, haloalkyl;
Above-mentioned alkyl arbitrarily can be a straight or branched; Preferred (C1-7) alkyl of above-mentioned alkyl arbitrarily and (C1-6) alkyl most preferably.
In the melts combine group of general formula (I), preferred:
X is NR1;
At least one is O among Y1 and the Y2; Y1 and Y2 are in particular O;
R1 is H, (C1-6) alkyl or halogen (C1-6) alkyl; R1 is in particular H, (C1-4) alkyl or halogen (C1-4) alkyl; R1 especially is H, (C1-3) alkyl or halogen (C1-3) alkyl; R1 is in particular H or amyl group; R1 especially is H.
The inhibitors of metalloproteinase compound is to suppress the active compound of metalloprotease (for example MMP).According to non-limitative example, described inhibitor compound can be at the external IC50s that demonstrates 0.1-10000 nmole scope, preferred 0.1-1000 nmole scope.
The melts combine base is the functional group of the metal ion on can the desmoenzyme avtive spot.For example, described melts combine base is in conjunction with the zinc binding moiety at zinc (II) ionic activity position in the MMP inhibitor.The melts combine base of general formula (I) is based on 5 ring structures and preferred glycolylurea base, the 1-H that most preferably-5 replaces, 3-H-imidazolidine-2,4-diketone.
The melts combine group of general formula (I) is connected with one or more other functional groups or side chain.Each functional group or side chain can comprise straight chain, branching and/or member ring systems.At least one functional group or side chain (preferred functional group) should provide the metalloprotease skeleton interactional hydrogen bond, and at least one functional group or side chain (preferred one or more functional groups) should carry out effective Van der Waals with the inferior point of enzyme and interact.Suitable group and/or side chain should be chosen in such a way, and promptly the gained compound plays the effect of inhibitors of metalloproteinase.
Have in the inhibitors of metalloproteinase compound or its salt or treatment treatment process that ester can be used for human or animal body of melts combine group of general formula (I).We disclose by the disease of one or more metalloprotease mediations or the treatment in the illness and have used.Each indication that inhibitors of metalloproteinase is described is represented independence of the present invention and specific embodiment above.We disclose especially by one or more MMPs, and the disease or the treatment in the illness of preferred MMP12 and/or MMP9 and/or MMP13 and/or MMP8 and/or MMP3 mediation are used; Especially using by the disease or the treatment in the illness of MMP12 or MMP9 mediation; Most particularly using by the disease or the treatment in the illness of MMP12 mediation.
We provide the disease of metalloprotease mediation or the methods of treatment of illness in one aspect of the method, this method comprises the step of warm-blooded animal being treated hydrolyzable ester in the inhibitors of metalloproteinase compound compound of significant quantity or its pharmaceutically acceptable salt or its body, wherein this inhibitors of metalloproteinase compound comprises melts combine group and one or more other functional group or side chain, it is characterized in that the melts combine base has above-mentioned general formula (I).
Especially, the disease of metalloprotease mediation or illness one or more MMPs that serve as reasons, the disease or the illness of preferred MMP12 and/or MMP9 and/or MMP13 and/or MMP8 and/or MMP3 mediation; Especially in disease or illness by MMP12 or MMP9 mediation.
The present invention also provides hydrolyzable ester in inhibitors of metalloproteinase compound or its pharmaceutically acceptable salt or its body to be used for the treatment of by the application in the medicine of the disease of one or more metalloprotease mediations or illness in preparation on the other hand, wherein this inhibitors of metalloproteinase compound comprises a melts combine group and one or more other functional group or side chain, it is characterized in that the melts combine base has above-mentioned general formula (I).
Especially, the disease of metalloprotease mediation or illness one or more MMPs that serve as reasons, the disease or the illness of preferred MMP12 and/or MMP9 and/or MMP13 and/or MMP8 and/or MMP3 mediation; Especially by the disease or the illness of MMP12 or MMP9 mediation; The most particularly by the disease or the illness of MMP12 mediation.
The disease or the illness of metalloprotease mediation comprise: asthma; Rhinitis; Chronic obstructive pulmonary disease (COPD); Sacroiliitis (such as rheumatoid arthritis and osteoarthritis); Atherosclerosis and restenosis; Cancer; Infringement and transfer; The disease that comprises disorganization; Relaxing in the hip replacement; Periodontopathy; Fibrotic conditions; Infarct and heart trouble; Liver and renal fibrosis; Endometriosis, the disease relevant with the extracellular matrix defective; Heart failure; Aortic aneurysm; With such as alzheimer's disease and the such CNS relative disease of multiple sclerosis (MS); Hemopathy.
The inhibitors of metalloproteinase compound that the present invention uses can be used as pharmaceutically acceptable salt to be provided.They comprise such as the salt of hydrochloride, hydrobromate, Citrate trianion and the so sour addition of maleate and the salt that forms with phosphoric acid and sulfuric acid.In one aspect of the method, suitable salt has: subsalt, and such as an alkali metal salt, for example sodium salt or sylvite; Alkaline earth salt, for example calcium salt or magnesium salts; Or organic amine salt, for example triethylamine.
The inhibitors of metalloproteinase compound can also be provided as hydrolyzable ester class in vivo.These compounds are hydrolysis and generate the pharmaceutically acceptable ester class of parent compound in human body.For example can be in test by intravenously to test animal give described compound and subsequently the verification test animal body fluid identify this class ester.Hydrolyzable ester class comprises methoxymethyl in the suitable body of carboxyl, and hydrolyzable ester class comprises formyl radical and ethanoyl, especially ethanoyl in the suitable body of hydroxyl.
In order to use in inhibitors of metalloproteinase compound of the present invention or its pharmaceutically acceptable salt or its body hydrolyzable ester to treat the Mammals that (comprising prophylactic treatment) comprises the people, generally described compound is mixed with pharmaceutical composition according to the standard drug embodiment.
Therefore, the present invention is provided for treating by the disease of one or more metalloprotease mediations or the pharmaceutical composition of illness on the other hand, it comprises hydrolyzable ester and medicine acceptable carrier in inhibitors of metalloproteinase compound or its pharmaceutically acceptable salt or its body, wherein this inhibitors of metalloproteinase compound comprises a melts combine group and one or more other functional group or side chain, it is characterized in that the melts combine base has above-mentioned general formula (I).
This pharmaceutical composition is used for the treatment treatment process of human or animal body.Be used for the treatment of in the disease or illness by one or more metalloprotease mediations.Each indication that inhibitors of metalloproteinase is described is represented independence of the present invention and specific embodiment above.We disclose especially by one or more MMPs, and the disease or the treatment in the illness of preferred MMP12 and/or MMP9 and/or MMP13 and/or MMP8 and/or MMP3 mediation are used; Especially using by the disease or the treatment in the illness of MMP12 or MMP9 mediation; Most particularly using by the disease or the treatment in the illness of MMP12 mediation.Special disease or illness comprise above-described those.
The present invention further provides a kind of disease of metalloprotease mediation or the methods of treatment of illness, this method comprises the pharmaceutical composition of warm-blooded animal being treated significant quantity, said composition comprises hydrolyzable ester and medicine acceptable carrier in inhibitors of metalloproteinase compound or its pharmaceutically acceptable salt or its body, wherein this inhibitors of metalloproteinase compound comprises melts combine group and one or more other functional group or side chain, it is characterized in that the melts combine base has above-mentioned general formula (I).
Especially, the disease of metalloprotease mediation or illness one or more MMPs that serve as reasons, the disease or the illness of preferred MMP12 and/or MMP9 and/or MMP13 and/or MMP8 and/or MMP3 mediation; Especially by the disease or the illness of MMP12 or MMP9 mediation; The most particularly by the disease or the illness of MMP12 mediation.Special disease or illness comprise above-described those.
Can according to standard manner, for example by oral, local, non-enteron aisle, suck, nose, vagina or rectal administration or give disease or the illness that pharmaceutical composition of the present invention is treated needs treatment by suction.For these purposes, can compound of the present invention be mixed with formulation by mode as known in the art, for example tablet, capsule, the aqueous solution or oil solution, suspensoid, emulsion, creme, ointment, gel, nose sprays, suppository, fine powder or suck with aerosol and non-enteron aisle with (comprising intravenously, intramuscular or infusion) aseptic aqueous solution or oil solution or suspension or there is not bacterial emulsion.
Except that compound of the present invention, pharmaceutical composition of the present invention can also contain one or more medicaments with the value that is used for the treatment of one or more diseases mentioned above or illness or with these medicament co-administereds (simultaneously or successively).
Generally with pharmaceutical composition of the present invention to people's administration, the dosage of for example make accepting every day is 0.5-75mg/kg body weight (and preferred 0.5-30mg/kg body weight).Can be as required with should fractionation dose every day, the exact amount of the compound of being accepted and route of administration depend on the patient's that treats body weight, age and sex and depend on disease specific or illness according to principle treatment as known in the art.
In general, unit dosage contains the The compounds of this invention of the 1mg-500mg that has an appointment.
Be used for the compound that of the present invention kind of inhibitors of metalloproteinase compound comprises that following general formula I I and III provide.The inhibitors of metalloproteinase compound of general formula I I and III (with hydrolyzable ester in its pharmaceutically acceptable salt or its body) is specially adapted to treat disease or the illness by MMP12 and/or MMP9 and/or MMP13 and/or MMP8 and/or MMP3 mediation; Especially by the disease or the illness of MMP12 or MMP9 mediation; The most particularly by the disease or the illness of MMP12 mediation.Special disease or illness comprise above-described those.
The compound of general formula I I
Figure A0281004100201
Wherein
X is selected from NR1, O, S;
Y1 and Y2 are independently selected from O, S;
Z is selected from O, S, SO, SO 2, SO 2N (R6), N (R7) SO 2, N (R7) SO 2N (R6);
M is 1 or 2;
A is selected from direct key, (C1-6) alkyl, (C1-6) haloalkyl or contains (C1-6) assorted alkyl that is selected from the heteroatom group of N, O, S, SO, SO2 or contains two heteroatom groups that are selected from N, O, S, SO, SO2 and opened by at least two carbon atoms separate;
R1 is selected from H, (C1-3) alkyl, haloalkyl;
R2 and R3 independently are selected from H, halogen (preferred fluorine), alkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkylaryl, alkyl-heteroaryl, assorted alkyl-aryl, assorted alkyl-heteroaryl, aryl-alkyl, the aryl-alkyl of mixing, heteroaryl-alkyl, heteroaryl-assorted alkyl, aryl-aryl, aryl-heteroaryl, heteroaryl-aryl, heteroaryl-heteroaryl, cycloalkyl-alkyl, Heterocyclylalkyl-alkyl, alkyl-cycloalkyl, alkyl-Heterocyclylalkyl separately with being;
R4 is selected from H, halogen (preferred fluorine), (C1-3) alkyl or haloalkyl independently of one another;
R6 is selected from H, alkyl, assorted alkyl, Heterocyclylalkyl, aryl, heteroaryl, alkaryl, alkyl-heteroaryl, assorted alkyl-aryl, assorted alkyl-heteroaryl, aralkyl, aryl-assorted alkyl, heteroaryl-alkyl, heteroaryl-assorted alkyl, aryl-aryl, aryl-heteroaryl, heteroaryl-aryl, heteroaryl-heteroaryl;
Each R2, R3 and R6 group can be chosen wantonly independently by one or more (preferred one) group and replace, these groups are selected from alkyl, assorted alkyl, aryl, heteroaryl, halogen, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, thiol, the alkyl sulfide hydroxyl, the aryl thiol, the alkyl sulfone, haloalkylsulfone, aryl sulfone, amino sulfone, N-alkylamino sulfone, N, N-dialkylamino sulfone, the amino sulfone of virtue, amino, the N-alkylamino, N, the N-dialkylamino, amido, the N-alkyl amido, N, N-dialkyl group amido, cyano group, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, amidino groups, N-aminosulfonyl-amidino groups, guanidine radicals, N-cyano group-guanidine radicals, the sulfo-guanidine radicals, 2-nitro-ethene-1, the 1-diamines, carboxyl, alkyl-carboxyl, nitro, carbamate;
R2 and R3 optionally can connect into and contain the ring that reaches 7 annular atomses or R2 and R4 and can connect into and contain the ring that reaches 7 annular atomses; Or R2 and R6 can connect into and contain the ring that reaches 7 annular atomses; Or R3 and R4 can connect into and contain the ring that reaches 7 annular atomses; Or R3 and R6 can connect into and contain the ring that reaches 7 annular atomses; Or R4 and R6 can connect into and contain the ring that reaches 7 annular atomses;
R5 contains one, two or three reach the monocycle of the ring structure of 7 annular atomses separately, two ring or three cyclic groups, they select cycloalkyl independently, aryl, Heterocyclylalkyl or heteroaryl, wherein each ring structure is optional is independently replaced by one or more substituting groups, these substituting groups are independently selected from halogen, hydroxyl, alkyl, alkoxyl group, halogenated alkoxy, amino, the N-alkylamino, N, the N-dialkylamino, alkyl sulfonyl amino, alkyl carboxyl amino, cyano group, nitro, thiol, the alkyl sulfide hydroxyl, alkyl sulphonyl, halogenated alkyl sulfonyl, the alkylamino alkylsulfonyl, carboxylicesters, the alkyl carboxylic acid ester, amino carboxyl, N-alkylamino-carboxyl, N, N-dialkylamino-carboxyl, any alkyl itself on wherein any substituting group can be chosen wantonly by one or more groups and replace, these groups are selected from halogen, hydroxyl, alkoxyl group, halogenated alkoxy, amino, the N-alkylamino, N, the N-dialkylamino, N-alkyl sulfonyl amino, N-alkyl carboxyl amino, cyano group, nitro, thiol, the alkyl sulfide hydroxyl, alkyl sulphonyl, N-alkylamino alkylsulfonyl, carboxylicesters, alkyl carboxyl, amino carboxyl, N-alkylamino carboxyl, N, N-dialkylamino carboxyl, carbamate;
When R5 is two rings or during three cyclic groups, each ring structure by direct key ,-mix alkyl, (C1-6) alkenyl, (C1-6) alkynyl, sulfone, CO, NCO, CON, NH, S, C (OH) of O-, (C1-6) alkyl, (C1-6) haloalkyl, (C1-6) be connected with the adjacent ring structure or condense with the adjacent ring structure;
R7 is selected from (C 1-6) alkyl, (C3-7) cycloalkyl, (C2-6) assorted alkyl, (C2-6) the assorted alkyl of ring;
Above-mentioned assorted arbitrarily alkyl is to contain the alkyl that the heteroatoms of the heteroatom group of one or more N of being independently selected from, O, S, SO, SO2 replaces, (heteroatom group is heteroatoms or heteroatoms group);
Above-mentioned Heterocyclylalkyl arbitrarily or heteroaryl contain the heteroatom group of one or more N of being independently selected from, O, S, SO, SO2;
Above-mentioned alkyl arbitrarily, alkenyl or alkynyl can be straight or brancheds; Except as otherwise noted, preferred (C1-7) alkyl of above-mentioned alkyl arbitrarily and most preferably (C1-6) alkyl.
The compound of general formula III
Figure A0281004100221
Wherein
X is selected from NR1, O, S;
Y1 and Y2 are independently selected from O, S;
Z is selected from NR2, O, S;
M is 0 or 1;
A is selected from direct key, (C1-6) alkyl, (C1-6) alkenyl, (C1-6) haloalkyl or contains (C1-6) assorted alkyl that is selected from the heteroatom group of N, O, S, SO, SO2 or contains two heteroatom groups that are selected from N, O, S, SO, SO2 and opened by at least two carbon atoms separate;
R1 is selected from H, (C1-3) alkyl, haloalkyl;
R2 is selected from H, alkyl, alkylhalide group;
R3 and R6 are independently selected from H, halogen (preferred F), alkyl, alkylhalide group, alkoxyalkyl, assorted alkyl, cycloalkyl, aryl, alkyl-cycloalkyl, alkyl-Heterocyclylalkyl, assorted alkyl-cycloalkyl, assorted alkyl-Heterocyclylalkyl, cycloalkyl-alkyl, cycloalkyl-assorted alkyl, Heterocyclylalkyl-alkyl, Heterocyclylalkyl-assorted alkyl, alkaryl, assorted alkyl-aryl, heteroaryl, miscellaneous alkyl aryl, assorted alkyl-heteroaryl, aralkyl, aryl-assorted alkyl, heteroaryl-alkyl, heteroaryl-assorted alkyl, two aryl, aryl-heteroaryl, heteroaryl-aryl, two heteroaryls contain the cycloalkyl or the Heterocyclylalkyl of 3 to 7 annular atomses, alkyl wherein, assorted alkyl, aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl can optionally selected basic one or more groups from following group replace described group hydroxyl, alkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, halogen, alkylhalide group, hydroxyalkyl, alkoxyl group, alkoxyalkyl, halogen alkoxyl group, halo alkoxy alkyl, carboxyl, carboxyalkyl, alkyl carboxyl, amino, N-alkylamino, N, N-dialkyl amido, alkylamino, alkyl (N-alkyl) amino, alkyl (N, N-dialkyl group) amino, amido, N-alkyl amido, N, N-dialkyl group amido, alkyl amido, alkyl (N-alkyl) amido, alkyl (N, N-dialkyl group) amido, alkyl carbamate, alkyl urea, mercaptan, sulfone, sulfonamino (sulfonamido), alkyl sulfonyl amino, Arenesulfonyl amino, sulfonamido, alkylhalide group sulfone, alkyl sulfide, aryl sulphur, the alkyl sulfone, aryl sulfone, amino sulfone, N-alkylamino sulfone, N, N-dialkyl amido sulfone, alkylamino sulfone, the arylamino sulfone, cyano group, alkyl cyano group, guanidine radicals, N-cyano group-guanidine radicals, the sulphur guanidine radicals, amidino groups, the amino inferior sulphur-amidino groups of N-, nitro, the alkyl nitro, 2-nitro-ethylidene-1,1-diamines;
R4 is selected from H, alkyl, hydroxyalkyl, alkylhalide group, alkoxyalkyl, halogen alkoxyl group, aminoalkyl group, acyl aminoalkyl, sulfane base;
R5 contains one, two or three are the monocycle of the ring structure of 3 to 7 annular atomses separately, two ring or three cyclic groups, they select cycloalkyl independently, aryl, Heterocyclylalkyl or heteroaryl, wherein each ring structure is optional is independently replaced by one or more substituting groups, these substituting groups are independently selected from halogen, thiolo, sulfane base, hydroxyl, alkyl-carbonyl, halogen alkoxyl group, amino, N-alkylamino, N, the N-dialkyl amido, cyano group, nitro, alkyl, alkylhalide group, alkoxyl group, the alkyl sulfone, amino-alkyl sulfinyl, alkylhalide group sulfone, alkyl amido, alkyl carbamate, alkyl urea, carbonyl, carboxyl, wherein the alkyl itself in any substituting group can optionally be replaced by one or more substituting groups, these substituting groups are independently selected from halogen, hydroxyl, amino, the N-alkylamino, N, N-dialkyl amido, alkyl sulfonyl amino, alkyl carboxyl amino, cyano group, nitro, mercaptan, alkyl sulfhydryl, alkyl sulfono, alkylamino sulfono, alkyl carboxylic acid ester's amido, the N-alkyl amido, N, N-dialkyl group amido, alkyl carbamate, alkyl urea, alkoxyl group, halogen alkoxyl group, carbonyl, carboxyl;
When R5 is two rings or during three cyclic groups, each ring structure by direct key, by-O-, by-S-, by-NH-, by (C1-6) alkyl, by (C1-6) haloalkyl, by (C1-6) mix alkyl, by (C1-6) alkenyl, by (C1-6) alkynyl, by sulfone, be connected with the adjacent ring structure or condense with the adjacent ring structure by carboxyl (C1-6) alkyl;
R2 and R4 can optionally be connected to form and comprise can connecting into up to the ring of 7 annular atomses or R3 and R6 and contain the ring that reaches 7 annular atomses;
Above-mentioned or following assorted arbitrarily alkyl is to contain the alkyl that the heteroatoms of the heteroatom group of one or more N of being independently selected from, O, S, SO, SO2 replaces, (heteroatom group is heteroatoms or heteroatoms group);
Above-mentioned or following Heterocyclylalkyl arbitrarily or heteroaryl contain the heteroatom group of one or more N of being independently selected from, O, S, SO, SO2; Above-mentioned or following alkyl arbitrarily, alkenyl or alkynyl can be straight or brancheds; Except as otherwise noted, preferred (C1-7) alkyl of above-mentioned alkyl arbitrarily and most preferably (C1-6) alkyl.
Should understand specified substituent on the The compounds of this invention and substituting group quantity are selected to avoid unwanted combination on the space.
Each exemplary compounds representative concrete and aspect independently of the present invention.
If rotophore is present in the compound of the present invention, we disclose all each optically-active forms of these compounds and combination and corresponding racemoid thereof as each specific embodiment of the present invention so.Can use known steps (with reference to Advanced Organic Chemistry: the 3rd edition: the author: J March, p104-107) racemoid is separated into each optically-active form, described step for example comprises that formation has the non-mapping derivative of suitable optically-active assisted class, separation and the described assisted class of cracking subsequently then.
Should understand the carbon atom that compound of the present invention can contain one or more asymmetric replacements.Exist these one or more asymmetric centers (chiral centre) can produce steric isomer and should understand the present invention in each case in the The compounds of this invention and can extend to all these class steric isomers, comprise enantiomorph and diastereomer and the mixture that comprises its racemic mixture.
Although have tautomer in the compound of the present invention, we disclose all each change forms of these compounds and have made up as each specific embodiment.
The invention provides and be used for the treatment of, wherein this inhibitors of metalloproteinase compound compound that is general formula I I or general formula III by hydrolyzable ester in the inhibitors of metalloproteinase compound of enzymatic disease of one or more metalloprotein or illness or acceptable salt of its medicine or the body.
The disease of metalloprotease mediation or the methods of treatment of illness have been the present invention further provides, this method comprises the step of warm-blooded animal being treated hydrolyzable ester in the inhibitors of metalloproteinase compound compound of significant quantity or its pharmaceutically acceptable salt or its body, wherein this inhibitors of metalloproteinase compound compound that is general formula I I or general formula III.
The present invention also provides hydrolyzable ester in inhibitors of metalloproteinase compound or its pharmaceutically acceptable salt or its body to be used for the treatment of by the application in the medicine of the disease of one or more metalloprotease mediations or illness in preparation on the other hand, wherein this inhibitors of metalloproteinase compound compound that is general formula I I or general formula III.
The present invention is provided for treating by the disease of one or more metalloprotease mediations or the pharmaceutical composition of illness on the other hand, it comprises hydrolyzable ester in inhibitors of metalloproteinase compound or its pharmaceutically acceptable salt or its body, wherein this inhibitors of metalloproteinase compound compound that is general formula I I or general formula III.
The present invention provides a kind of disease of metalloprotease mediation or the methods of treatment of illness on the other hand, this method comprises the pharmaceutical composition of warm-blooded animal being treated significant quantity, said composition comprises hydrolyzable ester and medicine acceptable carrier in inhibitors of metalloproteinase compound or its pharmaceutically acceptable salt or its body, wherein this inhibitors of metalloproteinase compound compound that is general formula I I or general formula III.
The metal deactivator compound of preparation general formula I I
Hydrolyzable ester is by describing below the method preparation of describing in (a) to (h) in the compound of general formula I I or its pharmaceutically acceptable salt or its body.Note a lot of related substanceses be commercial maybe can obtain maybe can be by currently known methods synthetic or in scientific and technical literature, find.
Compound exemplary providing in embodiment 1 to 23 by II.Wherein Z is selected from SO 2N (R6), N (R7) SO 2, N (R7) SO 2The compound of N (R6) provides in embodiment 1 to 5.Wherein Z is selected from SO, SO 2Provide in embodiment 6 to 20, wherein Z is selected from O, and the compound of S provides in embodiment 21 to 23.
(a) Y1 and the Y2 O that respectively does for oneself wherein, Z is that SO2N (R6) A is direct key, X is NR1, R1 is H, R2 is H, m is 1, R3 is H, R4 is H, and R5 and R6 be define among the general formula I I can be according to flow process 1 preparation.
When R6 is H, with the N of general formula I V 1The suitable SULPHURYL CHLORIDE of-BOC-D-diaminopropionic acid derivative and general formula V is reacted the sulfinyl amine that forms general formula VI in alkaline medium.Dealkylation reaction in acid medium reacts to corresponding urea with potassium cyanate, at last the compound of cyclisation acquisition general formula I I in acid medium.
When R6 is alkyl such as methyl, ethyl, propyl group, when sec.-propyl and normal-butyl, the N of general formula I V 2-alkyl-N 1-BOC-D-diaminopropionic acid is according to Andruszkiewics, R.:Pol.J.Chem, 62,257, (1988) preparation.
When R6 is non-essential substituted benzyl, methyl-benzyl, picolyl, during the methyl heteroaryl, the N of general formula I V 2-substituted amino acid is according to Helv.Chim.Acta, and 46,327, (1963) preparation.
Flow process 1:
Figure A0281004100251
This reaction IV-VI is optionally carrying out 1 to 24h in room temperature in the presence of the alkali to reflux temperature in suitable solvent.Preferred use at ambient temperature such as the such solvent of pyridine, dimethyl formamide, tetrahydrofuran (THF), acetonitrile or methylene dichloride with carry out 2-16 hour reaction times such as the such alkali of triethylamine, N-methylmorpholine, pyridine or alkaline carbonate or till detecting reaction by chromatography or spectrophotometry and finishing.Described in the reaction of the SULPHURYL CHLORIDE of general formula V and various primary amine class and secondary amine class such as the document and the variation of condition will be apparent to those skilled in the art.Commercially available or its synthetic being described in the document of all cpds of general formula V.The concrete derivative of general formula VI can prepare according to the procedure known to those skilled in the art.
(b) Y1 and the Y2 O that respectively does for oneself among the general formula I I, Z is SO2N (R6), and R6 is H, and A is direct key, and X is NR1, and R1 is H, and m is 1, and R2, and R3, R4 and R5 are that the compound that defines among the general formula I I can be according to flow process 1 preparation.
Wherein R2 is H, and R3 is that H and R4 are that the compound of alkyl or aryl can be by the alpha-amino group aldehyde preparation of the corresponding BOC N-protected of general formula III, according to Fehrentz, and JA, Castro, B., Synthesis, 676, (1983) preparation
Wherein R2 is an alkyl or aryl, and R3 is that H and R4 are that the compound of alkyl or aryl can be according to the corresponding m BOC N-protected alpha-amino group ketone preparation of the general formula VII that describes in the flow process 2.The alpha-amino group ketone of this BOC N-protected is according to Nahm, S, and Weinreb, SM:Tetrahedron Lett.22,3815, (1981) preparation, optionally when R6 is not H, according to Shuman, Robert T.US 4448717 A 19840515 prepare.
Flow process 2:
Figure A0281004100261
With compound and alkali metal cyanide and the volatile salt reaction (Strecker reaction) of general formula VII, obtain the corresponding glycolylurea of general formula VIIa.This racemic modification optionally separates after any one in three remaining steps: the sulfinyl amine compound of the carbamate of general formula VIIa and general formula I I on silica gel chromatography, by crystallization to after the amino intermediate deprotection.The amine intermediate can optionally be used for the compound of and SULPHURYL CHLORIDE coupling formation general formula I I direct at alkaline medium according to the description in the top sulfoamidoization.
The reaction of VII to VIIa preferably in airtight steel container in water-containing solvent carried out under 90-130 ℃ 3-16 hour or up to detect by chromatography or spectrophotometry the reaction finish till.With 1-4 times of excess cyanide salt, preferred normal cyanide salt of 1-2 and the doubly normal volatile salt of 2-6, the normal volatile salt of preferred 4-6 is handled, and obtains the glycolylurea of general formula VIIa.According to flow process 1 deprotection and alkylsulfonylization, obtain the compound of general formula I I then.
The amino aldehydes or ketones of general formula VII and its protection derivative are commercial, and other method can obtain alpha-amino group aldehyde and the ketone of general formula VII simultaneously, and the concrete derivative of general formula VIIa can prepare according to the procedure known to those skilled in the art.
(c) Y1 and the Y2 O that respectively does for oneself wherein, X is NR1 (R1=H), Z=N (R7) SO2, m=1, R4=H and R2, R3, R5 and R7 are the compound of the general formula I I that defines among the general formula I I, can be by R2 wherein, R3, R5, R7 and A respectively do for oneself the SULPHURYL CHLORIDE of the compound of the general formula VIII that defines among the general formula I I and general formula I X in polar aprotic solvent such as THF or DMF in the presence of alkali such as alkaline carbonate or alkyl amine or polyamines prepared in reaction.
Figure A0281004100271
The amine of general formula VIII is known in the literature and can buys from a lot of commercial undertakings.The concrete new variation of the compound of general formula VIII can be carried out according to the procedure known to those skilled in the art.The SULPHURYL CHLORIDE of general formula I X can be by the sulfide or the disulphide preparation of oxychlorination general formula X, and wherein R8 is group such as hydrogen, sec.-propyl, benzyl or sulfide, so that general formula X comprises symmetric disulphide.
The sulfide of general formula X can by halfcystine or Gelucystine (R2, R3=H) and its ester by with alkali metal cyanate and strong acid such as potassium cyanate and the preparation of hydrochloric acid subsequent treatment.In addition, the sulfide of general formula X can apply the condition preparation of describing in the conversion of VII to VIIa in above-mentioned (a) by the ketone of mutual-through type XI.
(d) Y1 and the Y2 O that respectively does for oneself wherein, Z is SO 2, R2 be the A that defines among the general formula I I be direct key with R5 comprise the nitrogen that directly is connected with Z general formula I I compound can by R5 wherein be the compound of the general formula I vb that defines among the general formula I I and wherein X and m be the known compound prepared in reaction of the general formula Vb that defines among the general formula I I:
This reaction is preferably optionally carrying out 1 to 24h in envrionment temperature in the presence of the alkali to reflux temperature in suitable solvent.Preferred use at ambient temperature such as the such solvent of pyridine, dimethyl formamide, tetrahydrofuran (THF), acetonitrile or methylene dichloride with carry out 2-16 hour reaction times such as the such alkali of triethylamine, N-methylmorpholine, pyridine or alkaline carbonate or till detecting reaction by chromatography or spectrophotometry and finishing.Described in the reaction of the SULPHURYL CHLORIDE of general formula V and various primary amine class and secondary amine class such as the document and the variation of condition will be apparent to those skilled in the art.Commercially available or its synthetic being described in the document of all cpds of general formula V.The reaction of the SULPHURYL CHLORIDE of general formula Vb and various primary and secondary amine has been described in the document and the various variations of condition are conspicuous for those skilled in the art.
General formula Vb compound synthetic is as document described in and can prepare (Mosher, J.:J.Org.Chem.23,1257 (1958) by for example halfcystine or homocysteine.
Be easy to compound by mutual-through type Va and carry out oxidation chlorination, wherein prepare the SULPHURYL CHLORIDE of general formula Vb described in R2 such as the general formula I I, m=1 wherein, (Griffith described in X=NR1 (R1=H) and R2 such as the general formula I I, O.:J.Biol.Chem., 1983,258,3,1591).
(e) compound that can be by making general formula VIb, wherein K is with the compound of general formula VIIb, wherein G is the compound that reaction prepares general formula I I described in sulfhedryl (SH), X and m such as the general formula I I described in leaving group (for example muriate or sulphonate) and R5 such as the general formula I I, Y1 and the Y2 O that respectively does for oneself wherein, Z is S, and X and R5 such as general formula I I
This reaction is preferably carried out having to exist and having under the situation that for example the such suitable solvent of DMF exists such as diethyl isopropylamine or the such alkali of cesium carbonate.
In addition, can according to the mode identical with method (e), by making general formula VIb and VIIb compound, wherein the K among the compound VI b is that on behalf of leaving group, G among sulfhedryl (SH) or hydroxyl and the general formula VIIb react compound among the preparation method (e).
(f) can by use such as the end product in the such oxygenant oxidation method (e) of superoxide reagent, preferred metachloroperbenzoic acid or ozone and wherein X be the compound that S prepares general formula I I, Y1 and the Y2 O that respectively does for oneself wherein, Z is SO2 or S (O), and described in X, A and R5 such as the general formula I I.
(g) can be in the sealed vessel under 40-80 ℃ by making general formula X Ib compound, wherein described in R2, R3, R4, R5 and A such as the general formula I I in protonic solvent, preferably the compound that prepared general formula I I under the situation that the ethanolic soln of excessive volatile salt and potassium cyanate exists with ammonium salt and cyanide salt reaction in 4-24 hour arranged, Y1 and the Y2 O that respectively does for oneself wherein, X is NR1 (R1=H), m is 1, and described in R2, R3, R4, R5 such as the general formula I.
Be easy in aprotic solvent by with the sulfonamides of excessive alkaline purification general formula X II, wherein R3 be described in H and R5 such as the general formula I I and then with the ester class of general formula X III, wherein R to be alkyl or aryl residue and R2 prepare the ketone of general formula X Ib as processing as described in the general formula I I.Preferred condition is the normal lithium alkali of 2-3, as LDA or hexamethyldisilazane lithium or butyllithium with in the dry ether solvent as tetrahydrofuran (THF).
Figure A0281004100302
Can also by use such as the ketone of such alkali of Tetrabutyl amonium bromide and general formula X V, wherein R2 is that alkyl or aryl is handled the-sulfinic acid ester class of general formula X IV, wherein R5 is the ketone that aryl described in general formula I I or heteroaryl prepare general formula X Ib, respectively do for oneself alkyl or form ring of R3 and R4 wherein, R5 is that aryl or heteroaryl and R2 are alkyl or aryl (J.Org.Chem.1985 such as Crandall, (8) 50,1327-1329).Then by introducing R3 and R4 with alkylogen or the reaction of alkyl dihalo-.This reaction is preferably carried out down and under having such as salt of wormwood or cesium carbonate and the situation that has suitable solvent, for example DMF or DMSO to exist at 50-100 ℃.
Figure A0281004100303
(h) compound of general formula I I, Y1 and the Y2 O that respectively does for oneself wherein, X is NR1 (R1=H), and Z is S or O, and R2, and R3, R4, R5 are be for general formula I I definition, can be by the compound of general formula VIIIc, R2 wherein, R3, R4, R5 and A be for general formula I I definition,
Figure A0281004100311
With ammonium salt and cyanide salt in protonic solvent, preferably under the situation that the ethanolic soln that excessive volatile salt and potassium cyanate are arranged exists 40-80 ℃ down reaction prepared in 4-24 hour.
Can be easily by halogenated ketone with general formula X c, wherein R2 is the mercaptan that the described and excess base of general formula I I is handled general formula I Xc, wherein R5 and A are described in the general formula I I, prepare the ketone of general formula VIIIc.
Figure A0281004100312
The metal deactivator compound of preparation general formula III
Hydrolyzable ester can prepare by the description in following (a) to (h) in the compound of general formula III or its pharmaceutically acceptable salt or its body.Should notice that a lot of relevant initial substances are commercially available, otherwise be exactly available or synthetic or in scientific and technical literature, find by currently known methods.(X, Y1, Y2, Z, m, A and R1-R6 define in the compound of following general formula III).
The compound of general formula III is exemplary providing in embodiment 24 to 61, and wherein R5 is that the compound of dicyclo or three cyclic groups provides in embodiment 24 to 39.Wherein R5 is that the compound of monocyclic groups provides in embodiment 40 to 61.If do not particularly point out, use the intermediate of describing in commercial initial substance or table 2 and 3.
(a) compound of general formula III can be converted into salt by currently known methods, the acceptable salt of medicine particularly, and vice versa; The acceptable salt of the salt of the compound of general formula III, particularly medicine can be converted into different salt, particularly medicine by currently known methods can be by the salt that is subjected to.
(b) compound of general formula III; wherein Z=O and R4=H; can be by compound and the compound of general formula III or appropriate protection form (shown in the flow process I) reaction of general formula III a compound of general formula I I, preparation optionally forms hydrolyzable ester in acceptable salt of its medicine or the body then:
Flow process 1:
Figure A0281004100321
The compound of the aldehydes or ketones of general formula I Ia and general formula III a is handled under from room temperature to reflux temperature in temperature with alkali in suitable solvent.Preferred basic solvent combination comprises aliphatic amine such as Trimethylamine e, and tetramethyleneimine or piperidines are at solvent such as methyl alcohol, ethanol, tetrahydrofuran (THF), in acetonitrile or the dimethyl formamide, add water dissolution reagent (Phillips, AP and Murphy in case of necessity, JG, 1951, J.Org.Chem. 16); Or hexamethyldisilazane lithium (Mio, S et al, 1991, Tetrahedron in tetrahydrofuran (THF) 47: 2121-2132); Or hydrated barta eight hydrates (Ajinomoto KK, 1993, Japanese Patent 05097814) in Virahol-water.
Preferably when preparing compound of the present invention with this method, R3, R5 or R6 do not contain other functional group, such as aldehydes, ketone, halo group or those skilled in the art well-known have disturb key to form reaction, competition or suppress any other group that key forms the ability of reaction with it.
Should understand many related raw materials and be purchased otherwise be exactly available maybe can be synthetic or can in scientific literature, find by currently known methods.
In order to prepare the compound of general general formula III a (R6 as mentioned described), can make general formula III a, wherein R6 is the compound of H and suitable aldehydes or ketones reaction, subsequent dewatering and the two keys that produce with the well-known method reduction of those skilled in the art then.
(c) can also be as to preparation compound of the present invention, wherein Z=O, R4=H and X=N or NR1, especially its specific steric isomer as described in 2 kinds in 4 kinds of possible steric isomers in following reaction process 2 and 3.
Flow process 2:
Flow process 3:
Figure A0281004100332
With the acrylate derivative of general formula I V as raw material, through glycols VIa or Vib carry out asymmetric Epoxidation, water carries out regional selective opening or asymmetric dihydroxy subsequently.According to the difference of chiral auxiliary(reagent) in epoxidation or the dihydroxy, can obtain general formula VIa or VIb glycols shown in steric isomer or its enantiomorph.(for example, Ogino, Y. etc., 1991, Tetrahedron Lett. 32(41): 5761-5764; Jacobsen, E.N. etc., 1994, Tetrahedron, 50(15): 4323-4334; Song, C.E. etc., 1997, Tetrahedron Asymmetry, 8(6): 841-844).Handle and carry out the ruthenium tetroxide catalyzed oxidation subsequently and obtain epithio esters of gallic acid VIIa and VIIb with organic bases and thionyl chloride.
By handle with the dimethyl formamide solution of sodiumazide, careful hydrolysis Hemisulphate intermediate and the epithio esters of gallic acid of general formula VIIa and VIIb is changed into the hydroxyl nitride (reaction process 3) of general formula VIIIa and VIIIb before the water operation is arranged subsequently.(Gao，Sharpless，1988，J.Am.Chem.Soc.， 110：7538；Kim，Sharpless，1989，Tetrahedron?Lett.， 30：655)。The hydroxyl nitride of hydrolysis general formula VIIIa and VIIIb also is reduced into beta-hydroxy-a-amino acid (not showing in the reaction process 3), preferably uses the THF solution hydrolysis of LiOH, and methyl alcohol or the organic phosphine solution with hydrogen sulfide, magnesium reduces through the Si Tuoding step subsequently.When using the water-bearing media solution-treated of cyanate and acid, beta-hydroxy-a-amino acid produces the compound of general formula I a successively.
(d) can also be as to preparation compound of the present invention as described in 2 kinds in 4 kinds of possible steric isomers in reaction process 2 and 3, wherein Z=O and R4 are not H, especially its specific steric isomer.Epoxide that can be by making the general formula V in the reaction process 2 and the alcohol reaction of general formula R 4-OH, produce alcohols and prepare these compounds.Subsequently by changing into nitride (Thompson, A.S. etc., 1993, J.Org.Chem. with phosphorus hydrazoic acid (phosphoazidate) 58(22): 5886-5888) obtain the ether analogs thing of the azido-ester class VIIIa in the reaction process 3, it is carried in the end product described in the step (c).Radicals R 4 and radicals R 3, R5 and R6 in can due care alcohols R4-OH.Can behind the hydantoins that changes into general formula I a, remove protecting group as final step.
(e) can also be as to preparation compound of the present invention as described in 2 kinds in 4 kinds of possible steric isomers in reaction process 2 and 3, wherein Z is that S or NR2 and Y1 and/or Y2 are O, especially its specific steric isomer.Can be by using thio-alcohol R4-SH or amine R4-NH 2Make the epoxide open loop (reaction process 2) of general formula V and after this carry out as carrying out similar synthetic these compounds that are converted as described in to alcohols VIIIa and VIIIb in the reaction process 3.When using the amine of R4-NH2, necessary N-protected intermediate alkamine especially needs when radicals R 4 is positive alkyl so especially.
(f) can also be as to preparation compound of the present invention as described in 2 kinds in 4 kinds of possible steric isomers in reaction process 2 and 3, wherein X is that S and Y1 and/or Y2 are O, especially its specific steric isomer.Epithio esters of gallic acid that can be by making general formula VIIa or VIIb or the alpha-hydroxy esters class of general formula VIa prepare these compounds (1997, Japanese Patent No. JP09025273) through its sulfonic acid esters and thiocarbamide or acid-respons.
Acrylate derivative (for example, van Heerden, P.S. etc., 1997, J.Chem.Soc., the Perkin Trans. that extensively obtains general formula I V by the phosphorus or the phosphate derivatives of aldehydes and acetate by Wittig or Homer-Emmons reaction for example 1(8): 141-1146).
(g) can in the encloses container under 50-100 ℃,, suitable aldehydes or ketones that replaces of general formula I Id and volatile salt and potassium cyanide prepare compound of the present invention, wherein X=NR1 and R1=H in 4-24 hour in water alcohol by being reacted.
Some aldehydes of general formula I Id or the preparation method of ketone are as described below:
Marte，A.-M.et?al，Tetrahedron?Lett.，1990， 31(18)：2599-2602；
Kren，V.et?al，1993，J.Chem.Soc.，Chem.Commun.， 4：341-343；
Schmittel，M.et?al，1990，Angew.Chem.， 102(10)：1174-1176；
Chakraborty，R.et?al，1992，Synth.Commun.， 22(11)：1523；
Harder，T.et?al，1994，Tetrahedron?Lett.， 35(40)：7365-7368；
Ruder，S.M.，1992，Tetrahedron.Lett.， 33(9)：2621-2624；
Maeda，H.et?al，1997，Chem.Pharm.Bull.， 45(11)：1729-1733；
Montana，J.G.et?al，1994，J.Chem.Soc.，Chem.Commun.， 19：2289-2290；
Davis，B.R.et?al，1992，Aust.J.Chem. 45(5)：865-875.
In described aldehydes or the ketone some can obtain by aldolisation (m=1, Z=O):
Mahrwald，R，et?al，1998，J.Am.Chem.Soc.， 120(2)：413-414；
Auerbach，R.A.，et?al，1988，Org.Synth.， VI：692；
Mukaiyama，T.；1977，Angew.Chem.，(Int.Ed.) 16；
Shimizu，N.et?al，1983，Bull.Chem.Soc.Jpn.， 56(12)：853；
Maruoka，K.et?al，1986，J.Am.Chem.Soc.， 108(13)：3827.
Listed in the known preparation method of general formula I Id compound such as the following table 1:
Table 1
Title (first is a formyl radical, even when " non-IUPAC ") CAS number
2-formyl radical-5-pyridin-3-yl furans ????38588-49-7
2-formyl radical-5-pyridine-2-base furans ????55484-36-1
5-formyl radical-2-Ben Ji oxazole ????92629-13-5
2-formyl radical-5-benzofurane ????13803-39-9
2-formyl radical-3-methyl-5-benzofurane ????160417-25-4
2-formyl radical-3-ethoxy carbonyl furans ????50800-39
2-formyl radical-5-phenyl-3, the 4-oxadiazole ????22816-01-9
2-formyl radical-5-Ben Ji oxazole ????96829-89-9
2-formyl radical-4-chloro-5-Ben Ji oxazole ????119344-57-9
2-formyl radical-4-chloro-2-pyridin-3-yl thiazole ????131969-58-9
2-formyl radical-5-pyridin-3-yl thiophene ????133531-43-8
2-formyl radical-5-pyridine-2-base thiophene ????132706-12-8
2-formyl radical-5-pyridin-4-yl thiophene ????21346-36-1
5-formyl radical-2-phenyl thiazole ????1011-40-1
5-formyl radical-4-chloro-2-phenyl thiazole ????108263-77-0
5-formyl radical-4-methyl-2-phenyl thiazole ????55327-23-6
2-formyl radical-5-phenyl thiophene ????19163-21-4
2-formyl radical-3-methyl-5-phenyl thiophene ????1604417-30-1
4-formyl radical-2-pyridine-2-base imidazoles ????279251-08-0
2-formyl radical-1-methyl-5 pyridin-3-yl pyrroles ????3614-77-5
4-formyl radical-2-pyridin-3-yl imidazoles ????279251-09-1
4-formyl radical-2-pyridin-4-yl 1,3, the 4-triazole ????42786-73-2
4-formyl radical-2-pyridin-4-yl imidazoles ????279251-10-4
4-formyl radical-5-methoxyl group-5-phenyl thiazole ????73725-36-7
4-formyl radical-5-ethoxy carbonyl-5-phenyl thiazole ????88469-73-2
4-formyl radical-5-ethoxy carbonyl-5-Ben Ji oxazole ????189271-85-0
2-formyl radical-3 methyl-5-phenyl 1,3, the 4-triazole ????89060-36-6
4-formyl radical-1-methyl-2-phenylimidazole ????94938-02-0
5-formyl radical-1-methyl-2-phenylimidazole ????94938-03-1
4-formyl radical-1-butyl-2-phenylimidazole ????198066-02-3
4-formyl radical-1-propyl group-2-phenylimidazole ????75378-63-1
5-formyl radical-1-butyl-2-phenylimidazole ????198065-92-8
2-formyl radical-1-methyl-4-phenylimidazole ????123511-51-3
4-formyl radical-2-phenyl-5-Jia Ji oxazole ????70170-23-9
2-formyl radical-5-phenyl 1,3, the 4-triazole ????26899-64-9
4-formyl radical-2-phenyl-5-chlorine imidazoles ????60367-52-4
4-formyl radical-2-phenylimidazole ????68282-47-3
4-formyl radical-2-phenyl-5-Methylimidazole ????68282-50-8
2-formyl radical-1-methyl-5-phenyl 1,3, the 4-triazole ????219600-03-0
2-formyl radical-4-phenylimidazole ????56248-10-3
2-formyl radical-1-methyl-4-phenylimidazole ????118469-06-0
2-formyl radical-5-phenylpyrazole ????52179-74-5
2-formyl radical-3-methyl-5-phenylpyrazole ????160417-28-7
2-formyl radical-3-ethoxy carbonyl-5-phenylpyrazole ????63202-77-7
2-formyl radical-5-morpholine-1-base furans ????3680-96-4
2-formyl radical-5-piperidines-1-base furans ????22868-60-6
2-formyl radical-5-cyclohexyl furans ????14174-51-7
2-formyl radical-3-methyl-5-cyclohexyl furans ????160417-27-6
(h) can also be according to following reaction process 4 described synthetic compounds of the present invention.Suitable target compound comprises 5-(phenylbenzene-4-base-hydroxyl-methyl)-imidazolidine (imidazolidie)-2 of the replacement described in the embodiment 8,4-diketone series and the 5-[4-phenoxy group-phenyl that replaces]-hydroxyl-methyl-imidazolidine-2,4-diketone series.
Committed step is the aldolisation (method C) that forms target compound.Synthetic intermediate in this reaction is by the 5-hydantoins (method A) of amino acid preparation and the aldehydes (method B) that passes through the Suzuki coupling, prepares in a conventional manner.Method C has also produced compound 1.With 2., they can be used for further transform Suzuki coupling (method D) and acid amides coupling (method E).
Aldolisation has obtained non-enantiomer mixture.By chromatography or in some cases by the Crystallization Separation racemoid.Can disassemble enantiomorph by chiral chromatography.
Flow process 4:
Figure A0281004100381
Can for example in following test, estimate the inhibitors of metalloproteinase compound:
Isolating enzyme test
The matrix metalloproteinase family that for example comprises MMP12, MMP13.
Can be as (2000) such as Parkar A.A. at Protein Expression and Purification, 20: express and purification of recombinant human MMP12 catalyst structure domain described in 152.The enzyme of purifying can be used for following monitoring inhibitor activity: under the situation that is with or without the inhibitor existence, use the synthetic test damping fluid of substrate Mac-Pro-Cha-G1y-Nva-His-Ala-Dpa-NH2 under RT (to contain 0.1MNaCl, 20mM CaCl 2, 0.040mM ZnCl and 0.05% (w/v) Brij 35 the 0.1MTris-HCl of pH 7.3) in MMP12 (50ng/ml final concentration) insulation 30 minutes.Measure activity by the fluorescence of measuring λ ex 328nm and λ em 393nm place.Following calculating suppresses per-cent: suppress % and equal [fluorescence+ Inhibitor-fluorescence Background] divided by [fluorescence- Inhibitor-fluorescence Background].
Can be as [V.Knauper etc. (1996) The Biochemical Journal such as Knauper 271: 1544-1550 (1996)] described expression and purification of recombinant human proMMP13.The enzyme of purifying can be used for following monitoring inhibitor activity: use 1mM aminophenyl mercury acid (APMA) that the proMMP13 of purifying is activated 20 hours down at 21 ℃; Under the situation that is with or without the inhibitor existence, use synthetic substrate ayapanin-4-yl) ethanoyl .Pro.Leu.Gly.Leu.N-3-(2, the 4-dinitrophenyl)-L-2,3-diamino propionyl .Ala.Arg.NH 2In the test damping fluid under 35 ℃ (the 0.1M Tris-HCl that contains the pH 7.5 of 0.1M NaCl, 20mMCaCl2,0.02mM ZnCl and 0.05% (w/v) Brij 35) activatory MMP13 (11.25ng/ test) is incubated 4-5 hour.Measure activity by the fluorescence of measuring λ ex 328nm and λ em393nm place.Following calculating suppresses per-cent: suppress % and equal [fluorescence+ Inhibitor-fluorescence Background] divided by [fluorescence- Inhibitor-fluorescence Background].
Can use for the best substrate of specific MMP and buffer conditions, for example as (1992) FEBS Lett.296 (3) such as C.GrahamKnight: the pro MMPs that as described in the 263-266 similar scheme is used for other expression and purifying.
The Adamalysin family that for example comprises TNF convertase
Use partially purified isolating enzyme test assessing compound to suppress the ability of proTNF α convertase, described enzyme is available from as (1994) Nature such as K.M.Mohler 370: the described THP-1 film of 218-220.By 26 ℃ and be with or without use under the situation that test compounds exists substrate 4 ', 5 '-dimethoxy-fluorescein base Ser.Pro.Leu.Ala.Gln.Ala.Val.Arg.Ser.Ser.Ser.Arg.Cys (4-(3-succinimide-1-yl)-fluorescein)-NH 2(contain 0.1% (w/v) Triton X-100 and 2mMCaCl at the test damping fluid 2The 50mM Tris HCl of pH7.4) partially purified enzyme insulation measured the activity and the inhibition situation thereof of this purifying enzyme in 18 hours.Except that using λ ex 490nm and λ em 530nm, MMP13 is measured the amount that suppresses.Following synthetic substrate.The peptide moiety of this substrate is assemblied on the Fmoc-NH-Rink-MBHA-polystyrene resin or by standard method with manual mode is assemblied on the automatic peptide synthesizer, described standard method comprises uses Fmoc-amino acid and O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-phosphofluoric acid urine (uronium hexafluorophosphate) are (HBTU) as coupling agent and 4-or doubly excessive Fmoc-amino acid and the HBTU of 5-at least.To Ser 1And Pro 2Carry out double couple crosslinking.Use following side chain protected strategy; Ser 1(butyl), Gln 5(trityl), Arg 8,12(Pmc or Pbf), Ser 9, 10,11(trityl), Cys 13(trityl).After the assembling, remove the terminal Fmoc-protecting group of N-by handle Fmoc-peptidyl-resin with DMF.By 70 ℃ down with 1.5-2 normal 4 ', 5 '-dimethoxy-fluorescein-4 (5)-carboxylic acid [Khanna﹠amp; Ullman, (1980) Anal Biochem. 108: 156-161), the DMF solution with di-isopropyl carbodiimide and I-hydroxybenzotriazole activates in advance] handle and to make thus obtained amino-peptidyl-resin acidylate in 1.5-2 hour.Make dimethoxy fluorescein base-peptide deprotection then simultaneously and by handling and make its cracking from the resin with containing each trifluoroacetic acid of 5% of water and triethyl silicane.Grind and filter by evaporation, with ether and separate dimethoxy fluorescein base-peptide.Isolating peptide and 4-(N-maleimide amino)-fluorescein is reacted, by the RP-HPLC purified product and finally separate in containing the DMF of diisopropylethylamine by freeze-drying from acetic acid aqueous solution.Make the product characterization and carry out amino acid analysis by MALDI-TOF MS.
Natural substrate
Can use for example based on E.C.Arner etc., (1998) Osteoarthritis and Cartilage6:214-228; (1999) Journal of Biological Chemistry, 274 (10), the method for the disclosed technical scheme of 6594-6601 and wherein said antibody detect the activity as the The compounds of this invention of aggrecan degradation inhibitor.Can be as T.Cawston and A.Barrett (1979) Anal.Biochem. 99: the described mensuration of 340-345 plays the effect of the compound of inhibitor effect to collagenase.
In based on the cell/tissue activity test as suppress film sheddases, such as TNF The metal proteinase activity restraining effect of the promoting agent of convertase
Can use basically as (1994) Nature such as K.M.Mohler 370: the ELISA of the TNF that the described detection of 218-220 discharges estimates The compounds of this invention suppresses the cell processing of TNF α generation in the THP-1 cell ability.Can use suitable clone in a similar way and use and detect come off (shed) proteic suitable antibodies test such as N.M.Hooper etc. at (1997) Biochem.J. 321: the processing of other such membrane molecule described in the 265-279 or come off.
As the test of inhibition based on the promoting agent of the infringement of cell
Can be as A.Albini etc. at (1987) Cancer Research 47: measure The compounds of this invention suppresses cell migration in the infringement test ability described in the 3239-3245.
As the test that suppresses the active promoting agent of whole blood TNF sheddase
In the test of people's whole blood, estimate The compounds of this invention and suppress the ability that TNF α produces, wherein LPS is used to stimulate TNF α. discharge.With substratum (RPMI1640+ supercarbonate, penicillin, Streptomycin sulphate and glutamine) by dilution in 1: 5 available from volunteer's the heparinization (human blood of 10 units/ml) and down and humidification (5%CO at 37 ℃ 2/ 95% air) DMSO or the appropriate carrier solution with 20 μ l test compounds (in triplicate) was incubated (160 μ l) 30 minutes in the incubator, after this added 20 μ l LPS (intestinal bacteria 0111:B4; Final concentration 10 μ g/ml).Each test comprises that separately the dilute blood control group (6 holes/flat board) that is incubated with substratum or known TNF alpha inhibitor are as standard substance.Under 37 ℃ (humidification incubators), flat board is incubated 6 hours, centrifugal (2000rpm 10 minutes then; 4 ℃), collect blood plasma (50-100 μ l) and be kept in the 96 hole flat boards-70 ℃ under, pass through elisa assay TNF α concentration subsequently.
Test as the promoting agent that suppresses external cartilage degradation
Basically as K.M.Bottomley etc. at (1997) Biochem J. 323: the ability of aggrecan or the degraded of collagen protein composition in the The compounds of this invention of evaluation described in the 483-488 inhibition cartilage.
The pharmacokinetics test
In order to estimate the removing characteristic and the bioavailability of The compounds of this invention, use pharmacokinetics test in the body, above-mentioned synthetic substrate test or optionally HPLC or mass spectroscopy are used in this test.This is the test that a class can be used to estimate the compound clearance rate of certain limit kind.Animal (for example rat, marmoset) is put into the suitable container that contains the 10U heparin through the soluble preparation (such as 20%w/v DMSO, 60%w/vPEG400) of intravenously or orally give compound and at later time point (for example 5,15,30,60,120,240,480,720,1220 minutes) blood sampling.Obtain the blood plasma fraction after centrifugal and precipitate plasma proteins with acetonitrile (80%w/v final concentration).Under-20 ℃ after 30 minutes, by the centrifugation plasma proteins and use Savant traditional vacuum high speed thickener to be evaporated to the supernatant liquor fraction dried.To be deposited in and dissolve again in the test damping fluid and the synthetic substrate analysis of experiments compounds content of use subsequently.Briefly, the compound of estimating is made up compound concentration-response curve.Estimate the active and use of the serial dilution thing that dissolves the blood plasma extract again and consider that concentration-response curve of total diluted plasma factor calculates the amount of the compound that exists in the primitive plasma sample.
Interior evaluating
Test as the anti-TNF promoting agent
In rat, estimate the ability of The compounds of this invention as TNF alpha inhibitor in the body.Briefly, by suitable route, for example oral (p.o.), intraperitoneal (i.p.), subcutaneous (s.c.) give compound (6 rats) or pharmaceutical carrier (10 rats) to array male Wistar Alderley Park (AP) rat (180-210g).Use the CO of the concentration that progressively raises after 90 minutes 2Put to death rat and blood is put into 5 units of heparin sodium/ml blood by the back vena cava.Immediately blood sample is placed on ice and under 4 ℃ with 2000rpm centrifugal 10 minutes and with the plasma freezing collected under-20 ℃ to be used for the test that subsequently the human blood that LPS-is stimulated produces the effect of TNF α.The rat plasma sample is melted and in the flat board of 96U hole, respectively adds the pattern of 175 μ l sample to groups setting form.In each hole, add 50 μ l heparinization human bloods, mixing then and with flat board in 37 ℃ (humidification incubators) insulation 30 minutes down.In each hole, add LPS (25 μ l; Final concentration 10 μ g/ml) and again continue insulation 5.5 hours.Control wells is incubated with 25 independent μ l substratum.Then with 2000 rpm with centrifugal 10 minutes of flat board and go to 200 μ l supernatant liquors on the 96 hole flat boards and be chilled in-20 ℃ down so that subsequently by elisa assay TNF concentration.
The data analysis of being undertaken by the software that provides has calculated each compound/dosage:
Figure A0281004100421
Test as anti-arthritic
At (1977) J.Exp.Med. such as D.E.Trentham 146: and test is as the compound activity as anti-arthritic in the 857 defined collagen protein inductive sacroiliitis (CIA).In this model, the natural II collagen type that is dissolved in acid makes rat produce polyarthritis when being dissolved in the resulting solution form administration of Freund's incomplete adjuvant.Similar condition can be used for bringing out the sacroiliitis of mouse and primates.
Test as anticarcinogen
Can be basically as I.J.Fidler (1978) Methods in Cancer Research 15: 399-439 is described, for example use B16 clone (B.Hibner etc. make a summary described in 283 p75 in the 10th CI-EORTC symposial of in June, 1998 16-19 day Amsterdam) to estimate activity as the compound of anticarcinogen.
Test as the emphysema medicine
Can be basically as (1997) Science such as Hautamaki, 277: 2002 described evaluations are as the activity of the compound of emphysema medicine.
Explain the present invention now but the present invention is not limited to the following example:
The general analysis method:At Varian UnityRecord on Inova 400MHz or the Varian Mercury-VX300MHz instrument 1H-NMR spectrum.With chloroform-d ( _ H7.27ppm), methyl-sulphoxide-d6 ( _ H2.50ppm) or methyl alcohol-d 4( _ H3.31ppm) the center solvent peak as interior mark.In the Agilent 1100 LC-MS systems that the APCI ionization chamber has been installed, obtain the low resolution mass spectrum.
If explanation is not arranged in addition, then be purchased raw material or intermediate described in the use table 2 and 3
Embodiment 1
N-{[(4S)-2,5-dioxo alkyl imidazole base] methyl-4-(4-fluorophenoxy) benzsulfamide and
N-{[(4S)-2,5-dioxo alkyl imidazole base] methyl } [1,1 '-xenyl]-the 4-sulphonamide
I C 6H 4SO 2Cl ii HCl/ diox iii KCNO iv wt.HCl, 100 ℃
R=4-fluorophenoxy or R=phenyl
(100mg 0.5mmol) in the solution in the 2.5ml water that contains 0.04g (0.55mmol) yellow soda ash, adds the solution of SULPHURYL CHLORIDE (0.5mmol) in the 2.5ml diox to N-a-BOC-(S)-diaminopropionic acid.This solution is under agitation spent the night, between ethyl acetate (10ml) and about 20% citric acid (10ml), distribute, water fluoroacetic acid ethyl ester is extracted three times repeatedly, with the water washing of organic extract usefulness salt, evaporation, and with the 4N HCl processing in the resistates usefulness diox.This mixture is stirred 20min, evaporation and 40 ℃ of following vacuum-dryings 4 hours.Then, (0.08g, 0.85mmol) water-soluble cancellation, and adding 0.9g (1.1mmol) potassium cyanate are stirred this mixture 4 hours down at 100 ℃ with 3ml yellow soda ash with this resistates.After this stage, add the 1ml concentrated hydrochloric acid, under uniform temp, stirred 1 hour, then with its standing over night at room temperature.With crystal filter, with distilled water wash and dry (in case of necessity, using ethyl alcohol recrystallization) in a vacuum.
N-{[(4S)-2,5-dioxo alkyl imidazole base] methyl }-4-(4-fluorophenoxy) benzsulfamide
MS：m/z＝380.1
N-{[(4S)-2,5-dioxo alkyl imidazole base] methyl } [1,1 '-xenyl]-the 4-sulphonamide
MS：m/z＝346.1
1H?NMR：(DMSO)：3.00m(1.5H)，3.10m(0.6H)，(CH 2)，4.10m(1H，CH)，7.5m(3H)，7.70d(2H)，7.4s(4H).
Embodiment 2
The compound of preparation formula II, wherein Y1 is O, and Y2 is O, and X is NR1, and R1 is H, and R2 is H, and m is 1, and R3 is H, and R4 is H, and Z is SO 2N (R6), R6 are H, and (C1-4) alkyl, methyl-benzyl, or picolyl, A are that direct key and R5 can change.
This synthesizes parallel carrying out on manually operated 20-well plate.
Amino acid (20um) is dissolved in the 5ml water that contains 6.36mg (60um) w yellow soda ash.0.5ml solution is moved in each well with transfer pipet, then move into the 0.5ml dioxane solution that contains the corresponding SULPHURYL CHLORIDE of 20um.With this reaction mixture jolting at room temperature 18 hours.Handle in 5 minutes with 2ml methyl alcohol dilution and the 20mg Lewatite S100 (sour form) that is used in each well.Then, with all reaction mixtures filter, vacuum-evaporation, and will steam the 1ml 4N HCl that thing is used in the diox and handle 30min, vacuum-evaporation adds 0.5ml 0.5M wt. potassium cyanide solution also 100 ℃ of heating 3 hours down.Then after being cooled to room temperature, 10mg Lewatite S100 (sour form) is added in each well, then add 2ml methyl alcohol, handled 2 hours down at 80 ℃ in vacuum-evaporation and with trifluoroacetic acid.After the evaporation, resistates is used ethyl acetate-methyl alcohol gradient liquid (10%MeOH at the most) (purifying by flash chromatography on silica gel.Purity and molecular weight are monitored by HPLC-MS.The every well of yield: 0.5-1mg.
5-(the 2-methyl-thiazole-5-yl)-thiophene phenol-2-sulfonic acid (2,5-dioxo-imidazolidine-4-ylmethyl)-acid amides
LC-MS(APCI)M ++H +＝373.4(m/z)
3-(4-chloro-phenoxy group) N-(2,5-dioxo-imidazolidine-4-ylmethyl)-benzsulfamide
LC-MS(APCI)M ++H +＝396.8(m/z)
4-(4-chloro-phenoxy group) N-(2,5-dioxo-imidazolidine-4-ylmethyl)-benzsulfamide
LC-MS(APCI)M ++H +＝396.8(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-4-(4-methoxyl group phenoxy group)-benzsulfamide
Figure A0281004100453
LC-MS(APCI)M ++H +＝392.6(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-3-(4-methoxyl group phenoxy group)-benzsulfamide
Figure A0281004100454
LC-MS(APCI)M ++H +＝392.6(m/z)
5-(5-trifluoromethyl H-pyrazole-3-yl)-thiophene phenol-2-sulfonic acid (2,5-dioxo-imidazolidine-4-ylmethyl)-acid amides
Figure A0281004100461
LC-MS(APCI)M ++H +＝410.4(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl is right-4-tolyloxy-benzsulfamide
Figure A0281004100462
LC-MS(APCI)M ++H +＝376.4(m/z)
3-(3,4-two chloro-phenoxy groups)-N-(dioxo-imidazolidine-4-ylmethyl) benzsulfamide
LC-MS(APCI)M ++H +＝430.6(m/z)
4-(3,4-two chloro-phenoxy groups)-N-(dioxo-imidazolidine-4-ylmethyl) benzsulfamide
LC-MS(APCI)M ++H +＝430.6(m/z)
4 '-fluoro-xenyl-4-sulfonic acid (2,5-dioxo-imidazolidine-4-ylmethyl) acid amides
LC-MS(APCI)M ++H +＝364.4(m/z)
5-pyridine-2-base-thiophene-2-sulfonic acid (2,5-dioxo-imidazolidine-4-ylmethyl) acid amides
Figure A0281004100473
LC-MS(APCI)M ++H +＝353.4(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-4-(2-methoxyl group-phenoxy group)-benzsulfamide
LC-MS(APCI)M ++H +＝392.5(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-3-(2-trifluoromethyl-phenoxy group) benzsulfamide
Figure A0281004100481
LC-MS(APCI)M ++H +＝430.4(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-3-(4-trifluoromethyl-phenoxy group) benzsulfamide
LC-MS(APCI)M ++H +＝430.4(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-4-(4-trifluoromethyl-phenoxy group) benzsulfamide
Figure A0281004100483
LC-MS(APCI)M ++H +＝430.4(m/z)
4 '-trifluoromethyl-xenyl-4-sulfonic acid (2,5-dioxo-imidazolidine-4-ylmethyl)-acid amides
LC-MS(APCI)M ++H +＝414.4(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-4-oxy-o-cresyl-benzsulfamide
LC-MS(APCI)M ++H +＝376.4(m/z)
4-(3,5-two chloro-phenoxy groups)-N-(2,5-dioxo-imidazolidine-4-ylmethyl)-4-oxy-o-cresyl-benzsulfamide
Figure A0281004100492
LC-MS(APCI)M ++H +＝431.3(m/z)
4-(2-chloro-phenoxy group)-N-(2,5-dioxo-imidazolidine-4-ylmethyl)-benzsulfamide
Figure A0281004100493
LC-MS(APCI)M ++H +＝396.8(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-3-is to tolyloxy-benzsulfamide
LC-MS(APCI)M ++H +＝3?76.4(m/z)
4-(4-cyano group-phenoxy group)-N-(2,5-dioxo-imidazolidine-4-ylmethyl)-benzsulfamide
Figure A0281004100502
LC-MS(APCI)M ++H +＝3?87.4(m/z)
4-(4-cyano group-phenoxy group)-N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-methyl-benzsulfamide
LC-MS(APCI)M ++H +＝401.4(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-methyl-4-(4-trifluoromethyl-phenoxy group)-benzsulfamide
Figure A0281004100511
LC-MS(APCI)M ++H +＝444.4(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-ethyl-4-(4-trifluoromethyl-phenoxy group)-benzsulfamide
Figure A0281004100512
LC-MS(APCI)M ++H +＝458.4(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-sec.-propyl-4-(4-trifluoromethyl-phenoxy group)-benzsulfamide
Figure A0281004100513
LC-MS(APCI)M ++H +＝472.4(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-isobutyl--4-(4-trifluoromethyl-phenoxy group)-benzsulfamide
Figure A0281004100521
LC-MS(APCI)M ++H +＝486.5(m/z)
N-benzyl-N-(2,5-dioxo-imidazolidine-4-ylmethyl)-4-(4-trifluoromethyl-phenoxy group)-benzsulfamide
Figure A0281004100522
LC-MS(APCI)M ++H +＝520.5(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-pyridin-3-yl methyl-4-(4-trifluoromethyl-phenoxy group)-benzsulfamide
LC-MS(APCI)M ++H +＝521.5(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-4-(4-fluorophenoxy)-N-methyl benzenesulfonamide
LC-MS(APCI)M ++H +＝394.4(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-ethyl-4-(4-fluorophenoxy)-benzsulfamide
Figure A0281004100532
LC-MS(APCI)M ++H +＝408.4(m/z)
N-benzyl-N-(2,5-dioxo-imidazolidine-4-ylmethyl)-4-(4-fluorophenoxy)-benzsulfamide
Figure A0281004100533
LC-MS(APCI)M ++H +＝470.5(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-4-(4-fluorophenoxy)-N-pyridin-3-yl methyl benzenesulfonamide
LC-MS(APCI)M ++H +＝471.5(m/z)
4-(4-chlorophenoxy)-N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-methyl benzenesulfonamide
Figure A0281004100541
LC-MS(APCI)M ++H +＝410.5(m/z)
4-(4-chlorophenoxy)-N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-ethylbenzene sulphonamide
Figure A0281004100542
LC-MS(APCI)M ++H +＝424.88(m/z)
4-(4-chlorophenoxy)-N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-isopropyl benzene sulphonamide
LC-MS(APCI)M ++H +＝424.88(m/z)
N-benzyl-4-(4-chlorophenoxy)-N-(2,5-dioxo-imidazolidine-4-ylmethyl)-benzsulfamide
Figure A0281004100551
LC-MS(APCI)M ++H +＝486.9(m/z)
4-(4-chlorophenoxy)-N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-pyridin-3-yl methyl benzenesulfonamide
Figure A0281004100552
LC-MS(APCI)M ++H +＝487.9(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-methyl-4-is to the tolyloxy benzsulfamide
Figure A0281004100553
LC-MS(APCI)M ++H +＝390.4(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-ethyl-4-is to the tolyloxy benzsulfamide
LC-MS(APCI)M ++H +＝404.5(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-sec.-propyl-4-is to the tolyloxy benzsulfamide
Figure A0281004100561
LC-MS(APCI)M ++H +＝418.5(m/z)
N-benzyl-N-(2,5-dioxo-imidazolidine-4-ylmethyl)-4-is to the tolyloxy benzsulfamide
Figure A0281004100562
LC-MS(APCI)M ++H +＝466.5(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-pyridin-3-yl methyl-4-is to the tolyloxy benzsulfamide
Figure A0281004100563
LC-MS(APCI)M ++H +＝467.5(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-4-(4-methoxyl group-phenoxy group)-N-methyl benzenesulfonamide
LC-MS(APCI)M ++H +＝406.5(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-ethyl-4-(4-methoxyl group-phenoxy group) benzsulfamide
Figure A0281004100572
LC-MS(APCI)M ++H +＝420.5(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-sec.-propyl-4-(4-methoxyl group-phenoxy group) benzsulfamide
Figure A0281004100573
LC-MS(APCI)M ++H +＝433.5(m/z)
N-benzyl-N-(2,5-dioxo-imidazolidine-4-ylmethyl)-4-(4-methoxyl group-phenoxy group) benzsulfamide
LC-MS(APCI)M ++H +＝482.5(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-4-(4-methoxyl group-phenoxy group)-N-pyridine three ylmethyl benzsulfamides
LC-MS(APCI)M ++H +＝483.5(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-4-(pyridin-4-yl oxygen base) benzsulfamide
Figure A0281004100582
LC-MS(APCI)M ++H +＝363.5(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-methyl-4-(pyridin-4-yl oxygen base) benzsulfamide
LC-MS(APCI)M ++H +＝377.4(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-ethyl-4-(pyridin-4-yl oxygen base) benzsulfamide
LC-MS(APCI)M ++H +＝363.4(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-4-(pyridin-4-yl oxygen base) benzsulfamide
Figure A0281004100592
LC-MS(APCI)M ++H +＝363.5(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-4-(pyridin-4-yl oxygen base) benzsulfamide
Figure A0281004100593
LC-MS(APCI)M ++H +＝376.4(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-ethyl-4-(pyridine-2-base oxygen base) benzsulfamide
LC-MS(APCI)M ++H +＝391.4(m/z)
4-(5-chloropyridine 2-base oxygen base-N-(2,5-dioxo-imidazolidine-4-ylmethyl)-benzsulfamide
LC-MS(APCI)M ++H +＝397.8(m/z)
4-(5-chloropyridine-2-base oxygen base-N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-methyl benzenesulfonamide
LC-MS(APCI)M ++H +＝410.8(m/z)
4-(5-chloropyridine-2-base oxygen base)-N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-ethylbenzene sulphonamide
LC-MS(APCI)M ++H +＝425.8(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-N-ethyl-4-(5-fluorine pyrimidine-2-yloxy)-benzsulfamide
LC-MS(APCI)M ++H +＝409.8(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-4-(5-fluorine pyrimidine-2-yloxy)-N-methyl-benzsulfamide
LC-MS(APCI)M ++H +＝396.4(m/z)
N-(2,5-dioxo-imidazolidine-4-ylmethyl)-4-(5-fluorine pyrimidine-2-yloxy)-benzsulfamide
Figure A0281004100613
LC-MS(APCI)M ++H +＝3?82.4(m/z)
Embodiment 3
The flow process 2 preparation compounds that provide in the description according to the as above compound of mutual-through type II.
(a) prepare its initial substance (aldehydes or ketones)
Aldehyde is according to Fehrentz JA and Castro B, Synthesis, 676, program preparation of describing in (1983).Ketone is according to Nahm S and Weinreb SM:Tetrahedron Lett.22, and 3815, program preparation of describing in (1981).
(b) preparation intermediate glycolylurea
Aldehydes or ketones (5mmol) is dissolved in 50% water-ethanol (10ml), and 0.55g (10mmol) sodium cyanide and 2.7g (25mmol) volatile salt are heated to 80 ℃ in sealed tube, heated 6 hours.Then with its cooling, with pH regulator to 4 and vacuum-evaporation.Resistates is distributed between water (10ml) and the ethyl acetate, and water is extracted 3 times with ethyl acetate again, evaporate then and separate diastereomer by silica gel column chromatography (gradient TBME-methyl alcohol 0-10%MeOH).Be prepared as follows glycolylurea.
R-1-(2,5-dioxo alkyl imidazole-4-S-the yl)-ethyl carbamic acid tert-butyl ester
LC-MS (APCI) :) M ++ H +=244.4) M +-56 (isobutylidenes) 188.6) M +-BOC=144.4 (main peak)
1H-NMR(CDCl 3.ppm)：1.23d(3H)，1.45s(9.1H)，4.36m(1.1H)，5.30bs(1.1H)，10.1bs(1.3H)
R-1-(4-methyl-2,5-dioxo alkyl imidazole-4-S-yl) ethyl carbamic acid
Figure A0281004100622
LC-MS (APCI) :) M ++ H +=258.3) M +-56 (isobutylidenes) 202.3) M +-BOC=158.3 (main peak)
1H-NMR(CDCl 3.ppm)：1.22d(3H)，1.44s(9.2H)，1.58s(3.1H)，3.95m(0.9H)，5.5bs(1.5H)，7.9bs(0.8H)
R-1-(4-methyl-2,5-dioxo alkyl imidazole-4-R-yl) the ethyl carbamic acid tert-butyl ester
Figure A0281004100631
LC-MS (APCI) :) M ++ H +=258.3) M +-56 (isobutylidenes) 202.3) M +-BOC=158.3 (main peak)
H-NMR(CDCl 3.ppm)：1.29d(3H)，1.54s(9.1H)，1.50s(2.95H)，4.25m(1.1H)，5.5bs(1.8H)，7.9bs(0.6H)
R-1-(2,5-dioxo-4-phenylimidazolidines,-4-S-yl)-ethyl carbamic acid tert-butyl ester
Figure A0281004100632
LC-MS (APCI) :) M ++ H +=320.3) M +-56 (isobutylidenes) 264.3) M +-BOC=230.3 (main peak)
H-NMR(CDCl 3.ppm)：1.31d(3H)，1.35s(9.2H)，4.65m(0.9H)，6.10d(0.94H)，7.25m(3.2H)，7.60d(2.05H)
(2S)-2-[(4R)-2,5-dioxo alkyl imidazole-4-yl] tetramethyleneimine-1-carboxylic acid tert-butyl ester
LC-MS：M ++H +＝170.0(M +-BOC)
NMR：(CDCl 3.ppm)：1.26s(9H)，1.7-1.9m(3.37H)，2.1-2.2m(0.84H)，3.35-3.44m(1.82H)，4.1bs(1.1H)
(2S)-2-[(4S)-2,5-dioxo alkyl imidazole-4-yl] tetramethyleneimine-1-carboxylic acid tert-butyl ester
LC-MS：M ++H +＝170.0(M +-BOC)
H-NMR：(CDCl 3.ppm)：1.27s(9H)，1.65-2.0m(broad)，(4.47H)，3.55m(1.15H)，3.62m(0.55H)，4.4m(0.87H)
(2R)-2-[(4S)-2,5-dioxo alkyl imidazole-4-yl] tetramethyleneimine-1-carboxylic acid tert-butyl ester
LC-MS：M ++H +＝170.0(M +-BOC)
H-NMR：(CDCl 3.ppm)：1.47s(9H)，1.7-2.2m(broad)4.30H，3.6m(1.12H)，3.8m(078H，3.6m(1.1H)
(2R)-2-[(4R)-2,5-dioxo alkyl imidazole-4-yl] tetramethyleneimine-1-carboxylic acid tert-butyl ester
LC-MS：M ++H +＝170.0(M +-BOC)
H-NMR：(CDCl 3.ppm)：1.47s(9H)，1.7-2.2m(broad)4.30H，3.6m(1.12H)，3.8m(078H，3.6m(1.1H)，
(2R)-2-[(4S)-and 4-methyl-2,5-dioxo alkyl imidazole-4-yl] tetramethyleneimine-1-carboxylic acid tert-butyl ester
LC-MS：M ++H +＝183.1(M +-BOC)
H-NMR：(CDCl 3.ppm)：1.4s(9H)1.50s(3.2H)，1.65-2.1m(broad)4.20H，3.4m(1.1H)，3.5bs(0.78H，4.4m(0.94H)，
The deprotection of BOC protection glycolylurea is undertaken by 40% trifluoroacetic acid in DCM, and after being evaporated to drying, by ether sedimentation final compound 5-(1-aminoethyl) 5-alkyl I imidazolidine-2,4 diketone trifluoro-acetate.
R-5-(S-1-aminoethyl)-imidazolidine-2,4-diketone trifluoro-acetate
LC-MS(APCI)：M ++H +＝144.2(m/z)
R-5-(1-aminoethyl)-5-S-Methylimidazole alkane-2,4-diketone trifluoro-acetate
LC-MS(APCI)：M ++H +＝158.2(m/z)
R-5-(1-aminoethyl)-5-R-Methylimidazole alkane-2,4-diketone trifluoro-acetate
LC-MS(APCI)：M ++H +＝158.2(m/z)
R-5-(1-aminoethyl)-5-S-phenylimidazolidines,-2,4-diketone trifluoro-acetate
LC-MS(APCI)：M ++H +＝220.3(m/z)
(5R)-5-[(2S)-and tetramethyleneimine-2-yl] imidazolidine-2,4-diketone trifluoro-acetate
LC-MS(APCI)：M ++H +＝169.1(m/z)
(5R)-5-[(2R)-and tetramethyleneimine-2-yl] imidazolidine-2, the 4-diketone
LC-MS(APCI)：M ++H +＝169.1(m/z)
(5R)-5-[(2S)-and tetramethyleneimine-2-yl] imidazolidine-2, the 4-diketone
LC-MS(APCI)：M ++H +＝169.1(m/z)
(5S)-5-[(2S)-and tetramethyleneimine-2-yl] imidazolidine-2, the 4-diketone
LC-MS(APCI)：M ++H +＝169.1(m/z)
(5S)-the 5-methyl-[(2R)-and tetramethyleneimine-2-yl] imidazolidine-2, the 4-diketone
LC-MS(APCI)：M ++H +＝183.21(m/z)
(c) glycolylurea of preparation general formula I I
Synthesize and parallelly on 20 well plates carry out manual operation.
The corresponding SULPHURYL CHLORIDE of about 7.5umol in 0.5ml DCM is dropped in each well, then be dropped in about 15-20umol 5-(1-aminoethyl) the 5-alkyl imidazole alkane-2 among the 0.5ml DCM, 4-diketone trifluoro-acetate (if necessity adds a small amount of DMF so that it dissolves fully), and add 10mg diethylin methylated polystyrene.Each mixture jolting is spent the night, through 200mg filtered through silica gel (wash with the 3-5ml ethyl acetate, and monitor purity) by LC-MS.Solution evaporation is extremely dry, so that all desired compounds of enough purity to be provided.
4-R-(4-chlorophenoxy-N-(1-(2,5 dioxo alkyl imidazoles-4-S-yl)-ethyl) benzsulfamide
Figure A0281004100651
LC-MS(APCI)：M ++H +＝411.1(m/z)
4-R-(5-chloropyridine-2-oxygen base)-N-(1-(2,5-dioxo alkyl imidazole-4-S-yl)-ethyl) benzsulfamide
Figure A0281004100652
LC-MS(APCI)：M ++H +＝412.1(m/z)
R-N-(1-(2,5-dioxo-imidazolidine-S-4-yl) ethyl)-4-(pyridine-2-base oxygen base)-benzsulfamide
LC-MS(APCI)：M ++2H +＝378.9(m/z)
R-N-(1-(2,5-dioxo-imidazolidine-S-4-yl) ethyl)-4-(pyridin-4-yl oxygen base)-benzsulfamide
Figure A0281004100662
LC-MS(APCI)：M ++2H +＝378.9(m/z)
4-R-(4-cyano-benzene oxygen-N-(1-(2,5 dioxo alkyl imidazoles-4-S-yl)-ethyl) benzsulfamide
Figure A0281004100663
LC-MS(APCI)：M ++H +＝401.5(m/z)
4-R-(4-fluorophenoxy-N-(1-(2,5 dioxo alkyl imidazoles-4-S-yl)-ethyl) benzsulfamide
LC-MS(APCI)：M ++H +＝394.3(m/z)
4-R-(4-4-trifluoromethylphenopendant-N-(1-(2,5 dioxo alkyl imidazoles-4-S-yl)-ethyl) benzsulfamide
LC-MS(APCI)：M ++H +＝444.4(m/z)
4-R-(4-methylphenoxy-N-(1-(2,5 dioxo alkyl imidazoles-4-S-yl)-ethyl) benzsulfamide
LC-MS(APCI)：M ++H +＝389.43(m/z)
4-R-(4-methoxyl group phenoxy group-N-(1-(2,5 dioxo alkyl imidazoles-4-S-yl)-ethyl) benzsulfamide
LC-MS(APCI)：M ++H +＝406.4(m/z)
4-R-(4-phenoxy group-N-(1-(2,5 dioxo alkyl imidazoles-4-S-yl)-ethyl) benzsulfamide
Figure A0281004100674
LC-MS(APCI)：M ++2H +＝376.2(m/z)
R-N-(1-(4-methyl 2,5-dioxo-imidazolidine-4-S-yl)-ethyl-4-phenoxyphenylsulfonyhalides amine
Figure A0281004100681
LC-MS(APCI)：M ++H +＝390.4(m/z)
4-(4-chlorophenoxy (henoxy)-N-(1-(4-S-methyl-2,5-dioxo alkyl imidazole-4-R-yl)-ethylbenzene sulphonamide
Figure A0281004100682
LC-MS(APCI)：M ++H +＝423.4(m/z)
4-(5-chloropyridine base-2-oxygen base)-N-(1-(4-S-methyl-2,5-dioxo alkyl imidazole-4-R-yl)-ethylbenzene sulphonamide
Figure A0281004100683
LC-MS(APCI)：M ++H +＝424.4(m/z)
N-(1-(4-S-methyl-2,5-dioxo alkyl imidazole-4-R-yl)-ethyl)-4-(pyridine-2-base oxygen base) benzsulfamide
Figure A0281004100684
LC-MS(APCI)：M ++2H +＝392.4(m/z)
N-(1-(4-S-methyl-2,5-dioxo alkyl imidazole-4-R-yl)-ethyl)-4-(pyridine-2-base oxygen base) benzsulfamide
Figure A0281004100691
LC-MS(APCI)：M ++2H +＝392.4(m/z)
4-(4-cyano-benzene oxygen-N-(1-(4-S-methyl-2,5-dioxo alkyl imidazole-4-R-yl)-ethylbenzene sulphonamide
Figure A0281004100692
LC-MS(APCI)：M ++2H +＝415.4(m/z)
R-N-(1-(4-methyl 2,5-dioxo-imidazolidine-4-R-yl)-ethyl-4-phenoxyphenylsulfonyhalides amine
LC-MS(APCI)：M ++H +＝390.4(m/z)
4-(4-chlorophenoxy (henoxy)-N-(1-(4-R-methyl-2,5-dioxo alkyl imidazole-4-R-yl)-ethylbenzene sulphonamide
Figure A0281004100694
LC-MS(APCI)：M ++H +＝423.4(m/z)
4-(5-chloropyridine base-2-oxygen base)-N-(1-(4-R-methyl-2,5-dioxo alkyl imidazole-4-R-yl)-ethylbenzene sulphonamide
LC-MS(APCI)：M ++H +＝424.4(m/z)
N-(1-(4-S-methyl-2,5-dioxo alkyl imidazole-4-R-yl)-ethyl)-4-(pyridine-2-base oxygen base) benzsulfamide
LC-MS(APCI)：M ++2H +＝392.4(m/z)
N-(1-(4-S-methyl-2,5-dioxo alkyl imidazole-4-R-yl)-ethyl)-4-(pyridine-2-base oxygen base) benzsulfamide
Figure A0281004100703
LC-MS(APCI)：M ++2H +＝392.4(m/z)
4-(4-cyano-benzene oxygen-N-(1-(4-S-methyl-2,5-dioxo alkyl imidazole-4-R-yl)-ethylbenzene sulphonamide
LC-MS(APCI)：M ++H +＝415.4(m/z)
4-(4-fluorophenoxy-N-(1-(4-R-methyl-2,5-dioxo alkyl imidazole-4-S-yl)-ethylbenzene sulphonamide
LC-MS(APCI)：M ++H +＝407.4(m/z)
4-(4-4-trifluoromethylphenopendant-N-(1-(4-R-methyl-2,5-dioxo alkyl imidazole-4-S-yl)-ethylbenzene sulphonamide
Figure A0281004100713
LC-MS(APCI)：M ++H +＝458.4(m/z)
4-(4-methylphenoxy-N-(1-(4-R-methyl-2,5-dioxo alkyl imidazole-4-S-yl)-ethylbenzene sulphonamide
LC-MS(APCI)：M ++H +＝404.5(m/z)
4-(4-methoxyl group phenoxy group-N-(1-(4-R-methyl-2,5-dioxo alkyl imidazole-4-S-yl)-ethylbenzene sulphonamide
LC-MS(APCI)：M ++H +＝420.5(m/z)
4-(4-phenoxy group-N-(1-(4-R-methyl-2,5-dioxo alkyl imidazole-4-S-yl)-ethylbenzene sulphonamide
LC-MS(APCI)：M ++H +＝390.5(m/z)
4-(4-fluorophenoxy-N-(1-(4-R-methyl-2,5-dioxo alkyl imidazole-4-R-yl)-ethylbenzene sulphonamide
LC-MS(APCI)：M ++H +＝407.4(m/z)
4-(4-4-trifluoromethylphenopendant-N-(1-(4-R-methyl-2,5-dioxo alkyl imidazole-4-R-yl)-ethylbenzene sulphonamide
LC-MS(APCI)：M ++H +＝458.4(m/z)
4-(4-methylphenoxy-N-(1-(4-R-methyl-2,5-dioxo alkyl imidazole-4-R-yl)-ethylbenzene sulphonamide
Figure A0281004100731
LC-MS(APCI)：M ++H +＝404.5(m/z)
4-(4-methoxyl group phenoxy group-N-(1-(4-R-methyl-2,5-dioxo alkyl imidazole-4-R-yl)-ethylbenzene sulphonamide
Figure A0281004100732
LC-MS(APCI)：M ++H +＝420.5(m/z)
4-(4-phenoxy group-N-(1-(4-R-methyl-2,5-dioxo alkyl imidazole-4-R-yl)-ethylbenzene sulphonamide
Figure A0281004100733
LC-MS(APCI)：M ++H +＝390.5(m/z)
4-(4-chlorophenoxy)-N-(1-((2,5-dioxo-4-S-phenyl-imidazolidine-4-R-yl)-ethyl) benzsulfamide
LC-MS(APCI)：M ++H +＝486.8(m/z)
4-(5-chloropyridine-2-base oxygen base)-N-(1-((2,5-dioxo-4-S-phenyl-imidazolidine-4-R-yl)-ethyl) benzsulfamide
LC-MS(APCI)：M ++H +＝487.8(m/z)
N-(1-S-(2,5-dioxo-4-phenylimidazolidines,-4-R-yl)-ethyl-4-(pyridine-2-base oxygen base)-benzsulfamide
Figure A0281004100742
LC-MS(APCI)：M ++2H +＝454.6(m/z)
N-(1-S-(2,5-dioxo-4-phenylimidazolidines,-4-R-yl)-ethyl-4-(pyridin-4-yl oxygen base)-benzsulfamide
LC-MS(APCI)：M ++2H +＝454.6(m/z)
4-(4-cyano-benzene oxygen)-N-(1-((2,5-dioxo-4-S-phenyl-imidazolidine-4-R-yl)-ethyl) benzsulfamide
LC-MS(APCI)：M ++H +＝477.6(m/z)
4-(4-fluorophenoxy)-N-(1-((2,5-dioxo-4-S-phenyl-imidazolidine-4-R-yl)-ethyl) benzsulfamide
LC-MS(APCI)：M ++H +＝470.5(m/z)
4-(4-4-trifluoromethylphenopendant)-N-(1-((2,5-dioxo-4-S-phenyl-imidazolidine-4-R-yl)-ethyl) benzsulfamide
LC-MS(APCI)：M ++H +＝519.1(m/z)
4-(4-methylphenoxy)-N-(1-((2,5-dioxo-4-S-phenyl-imidazolidine-4-R-yl)-ethyl) benzsulfamide
Figure A0281004100754
LC-MS(APCI)：M ++H +＝466.4(m/z)
4-(4-methoxyl group phenoxy group)-N-(1-((2,5-dioxo-4-S-phenyl-imidazolidine-4-R-yl)-ethyl) benzsulfamide
LC-MS(APCI)：M ++H +＝482.4(m/z)
4-(4-phenoxy group)-N-(1-((2,5-dioxo-4-S-phenyl-imidazolidine-4-R-yl)-ethyl) benzsulfamide
LC-MS(APCI)：M ++H +＝452.5(m/z)
5-(1-{[4-(4-chlorophenoxy) phenyl] alkylsulfonyl } tetramethyleneimine-2-yl)-5-Methylimidazole alkane-2, the 4-diketone
LC-MS(APCI)：M ++H +＝450.5(m/z)
5-(1-{[4-(4-methoxyl group phenoxy group) phenyl] alkylsulfonyl } tetramethyleneimine-2-yl)-5-Methylimidazole alkane-2, the 4-diketone
Figure A0281004100771
LC-MS(APCI)：M ++H +＝446.2(m/z)
5-(1-{[4-(4-methylphenoxy) phenyl] alkylsulfonyl } tetramethyleneimine-2-yl)-5-Methylimidazole alkane-2, the 4-diketone
LC-MS(APCI)：M ++H +＝430.1(m/z)
5-(1-{[4-(4-fluorophenoxy) phenyl] alkylsulfonyl } tetramethyleneimine-2-yl)-5-Methylimidazole alkane-2, the 4-diketone
LC-MS(APCI)：M ++H +＝434.1(m/z)
(1-{[4-(4-cyano-benzene oxygen) phenyl] alkylsulfonyl } tetramethyleneimine-2-yl)-5-Methylimidazole alkane-2, the 4-diketone
Figure A0281004100782
LC-MS(APCI)：M ++H +＝441.1(m/z)
5-(1-{[4-(4-chlorophenoxy) phenyl] alkylsulfonyl } tetramethyleneimine-2-yl) imidazolidine-2, the 4-diketone
Figure A0281004100791
LC-MS(APCI)：M ++H +＝436.1(m/z)
5-(1-{[4-(4-fluorophenoxy) phenyl] alkylsulfonyl } tetramethyleneimine-2-yl) imidazolidine-2, the 4-diketone
Figure A0281004100792
LC-MS(APCI)：M ++H +＝420.1(m/z)
5-(1-{[4-(4-methylphenoxy) phenyl] alkylsulfonyl } tetramethyleneimine-2-yl) imidazolidine-2, the 4-diketone
Figure A0281004100801
LC-MS(APCI)：M ++H +＝416.1(m/z)
5-(1-{[4-(4-methoxyl group phenoxy group) phenyl] alkylsulfonyl } tetramethyleneimine-2-yl) imidazolidine-2, the 4-diketone
Figure A0281004100802
LC-MS(APCI)：M ++H +＝432.1(m/z)
5-(1-{[4-(4-cyano-benzene oxygen) phenyl] alkylsulfonyl } tetramethyleneimine-2-yl) imidazolidine-2, the 4-diketone
Figure A0281004100811
LC-MS(APCI)：M ++H +＝427.1(m/z)
Embodiment 4
With [(4R)-2,5-dioxo alkyl imidazole base] methane sulfonyl chloride, [(4S)-2,5-dioxo alkyl imidazole base] methane sulfonyl chloride or [(R)-2,5-dioxo alkyl imidazole base]-methane sulfonyl chloride and suitable uncle or secondary amine reaction obtain compound given below.All amine that use all are commercial.
Will be in the SULPHURYL CHLORIDE (0.060mmol) in the dry tetrahydrofuran (0.70mL), amine (0.060mmol), triethylamine (0.0084mL, 0.060mmol) at room temperature spend the night by stirring.(0.025g 0.030mmol) also spends the night this mixture jolting to add the polystyrene methyl isocyanate.(2 * 1mL) clean with tetrahydrofuran (THF) with this white suspension filtration and with solid.With filtrate evaporation, white solid is suspended in the water (5mL), on strainer, to collect, water (also spend the night 45 ℃ of following vacuum-dryings, obtains title compound by 2 * 1mL) washings, suction water outlet.
By being prepared as follows initial substance:
5-methyl-5-{[(phenmethyl) sulphur] methyl } imidazolidine-2, the 4-diketone
Second alcohol and water (315mL/135mL) is dropped in the steel cylinder.
Add 31.7g (0.175mol) dibenzylsulfide acetone, 22.9g (0.351mol) potassium cyanide and 84.5g (0.879mol) volatile salt.The reactor that this is airtight kept 3 hours in oil bath (bathing 90 ℃ of temperature) under acutely stirring.
This reactor with frozen water (0.5h) cooling, is evaporated to drying with yellow slurry, is distributed between 400mL water and the 700mL ethyl acetate solid residue and evaporation.Water is extracted with ethyl acetate (300mL).The organic phase that merges is washed dry (Na with saturated brine (150mL) 2SO 4), filter and be evaporated to drying.If product is non-crystallizable, then the 300ml methylene dichloride is added in the oil.Evaporation obtains product, is buff powder 43.8g (90%).
LC-MS(APCI)m/z?251.1(MH+).
1H?NMR(DMSO-d 6)δ：10.74(1H，s)；8.00(1H，s)；7.35-7.20(5H，m)；3.76(2H，s)；2.72，2.62(1H?each，ABq，J＝14.0Hz)；1.29(3H，s).
13C?NMR(DMSO-d 6)δ：177.30，156.38，138.11，128.74，128.24，126.77，62.93，37.96，36.39，23.15.
(5S)-and 5-methyl-5-{[(phenmethyl) sulphur] methyl } imidazolidine-2, the 4-diketone
By preparing title compound with 250mm * 50mm pillar chirality separation of racemic material on Dynamic Axial Compression PreparativeHPLC pillar.The stationary phase that uses is CHIRALPAK AD, elutriant=methyl alcohol, flow=89mL/min, temperature=room temperature, UV=220nm, sample concentration=150mg/mL, volume injected=20mL.
Retention time=the 6min of title compound.
Use 250mm * 4.6mm CHIRALPAK-AD pillar to carry out chiral purity analysis, flow=0.5mL/min, elutriant=ethanol, UV=220nm, temperature=room temperature available from Daicel.
Retention time=the 9.27min. of title compound
Purity is estimated as＞99%ee.
LC-MS(APCI)m/z?251.1(MH+).
[α] D＝-30.3°(c＝0.01g/mL，MeOH，T＝20℃).
1H?NMR(DMSO-d 6)δ：10.74(1H，s)；8.00(1H，s)；7.35-7.20(5H，m)；3.76(2H，s)；2.72，2.62(1H?each，ABq，J＝14.0Hz)；1.29(3H，s).
13C?NMR(DMSO-d 6)δ：177.30，156.28，138.11，128.74，128.24，126.77，62.93，37.96，36.39，23.15.
(5R)-and 5-methyl-5-{[(phenmethyl) sulphur] methyl } imidazolidine-2, the 4-diketone
By preparing title compound with 250mm * 50mm pillar chirality separation of racemic material on Dynamic Axial Compression PreparativeHPLC pillar.The stationary phase that uses is CHIRALPAK AD, elutriant=methyl alcohol, flow=89mL/min, temperature=room temperature, UV=220nm, sample concentration=150mg/mL, volume injected=20mL.
Retention time=the 10min of title compound.
Use 250mm * 4.6mm CHIRALPAK-AD pillar to carry out chiral purity analysis, flow=0.5mL/min, elutriant=ethanol, UV=220nm, temperature=room temperature available from Daicel.
Retention time=the 17.81min. of title compound
Chiral purity estimation＞99%ee.
LC-MS(APCI)m/z?251.0(MH+).
[α] D＝+30.3°(c＝0.01g/mL，MeOH，T＝20℃).
1H?NMR(DMSO-d 6)δ：10.74(1H，s)；8.00(1H，s)；7.35-7.20(5H，m)；3.76(2H，s)；2.72，2.62(1H?each，ABq，J＝14.0Hz)；1.29(3H，s).
13C?MR(DMSO-d 6)δ：177.31，156.30，138.11，128.74，128.25，126.77，62.94，37.97，36.40，23.16.
[(4S)-and 4-methyl-2,5-dioxo alkyl imidazole-4-yl] methane sulfonyl chloride
With (5S)-5-methyl-5-{[(phenmethyl) sulphur] methyl } imidazolidine-2,4-diketone (42.6g; 0.17mol) be dissolved in AcOH (450mL) and H 2In the mixture of O (50mL).This mixture is immersed in the ice/water-bath, blast Cl by this solution 2(g), the flow velocity of adjustments of gas so that temperature keep below+15 ℃.Behind the 25min, this solution becomes yellow-green colour and sample is extracted out to carry out LC/MS and HPLC analysis.Its explanation initial substance consumes.This yellow transparent solution was stirred 30 minutes, form colourless solution/slurry.
Keep+37 ℃ water-bath on rotatory evaporator, to remove with temperature solvent.Yellow solid is suspended in the toluene (400mL), and on same rotatory evaporator, removes and desolvate.Then thick product is suspended in the isohexane (400mL), and under agitation is warmed to+40 ℃, this slurry is cooled to room temperature, then by removing by filter insoluble product, with isohexane (6 * 100mL) washings, and under reduced pressure+50 ℃ of following dried overnight.So obtain yellow powder powder product.Obtain 36.9g (95%) title compound.
Purity (analyzing by HPLC)=99%, NMR supports this purity.
[α] D＝-12.4°(c＝0.01g/mL，THF，T＝20℃).
1H?NMR(THF-d 8)：δ9.91(1H，bs)；7.57(1H，s)；4.53，4.44(1H?each，ABq，J＝14.6Hz)；1.52(s，3H，CH 3).
13C?NMR(THF-d 8)：δ174.96；155.86；70.96；61.04；23.66.
[(4R)-and 4-methyl-2,5-dioxo alkyl imidazole-4-yl] methane sulfonyl chloride
According to the technology that [(4S)-4-methyl-2,5-dioxo alkyl imidazole-4-yl] methane sulfonyl chloride is described.
By (5R)-5-methyl-5-{[(phenmethyl) sulphur] methyl } imidazolidine-2, the 4-diketone (10.0g, 40mmol) initial.
Obtain 8.78g (96% yield) title compound.
Purity (analyzing)＞98%. by NMR
[α] D＝+12.8°(c＝0.01g/mL，THF，T＝20℃).
1H?NMR(THF-d 8)：δ9.91(1H，brs)；7.57(1H，s)；4.53，4.44(1H?each，ABq，J＝14.6Hz)；1.52(s，3H，CH 3).
13C?NMR(THF-d 8)：δ174.96；155.84；70.97；61.04；23.66.
Figure A0281004100841
Following table provides the amido of each compound of said structure.
Following table provides the amido of each compound of said structure
Figure A0281004100853
Figure A0281004100861
Figure A0281004100862
Following table provides the amido of each compound of said structure
N-[4-(4-chloro-phenoxy group)-phenyl]-C-((4S)-4-methyl-2,5-dioxo-imidazolidine-4-yl)-methane Sulphonamide
LC-MS(APCI)m/z?410(MH+).
1H?NMR(DMSO-d 6)：δ10.75(1H，s)；9.89(1H，s)；8.04(1H，s)；7.45-7.39(2H，m)；7.25-7.19(2H，m)；7.06-6.97(4H，m)；3.54(1H?from?ABq，J＝14.1Hz)；1.31(3H，s).
N-(4-benzyl-phenyl)-C-((4S)-4-methyl-2,5-dioxo-imidazolidine-4-yl)-amsacrine
LC-MS(APCI)m/z?374(MH+).
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；9.82(1H，s)；8.01(1H，s)；7.33-7.05(9H，m)；3.49，3.36(1H?each，ABq，J＝16.2Hz)；1.28(3H，s).
N-(4-benzoyl-phenyl)-C-((4S)-4-methyl-2,5-dioxo-imidazolidine-4-yl)-sulfonyl methane Amine
LC-MS(APCI)m/z?388(MH+).
1H?NMR(DMSO-d 6)：δ10.81(1H，s)；10.58(1H，s)；8.08(1H，s)；7.76-7.62(5H，m)；7.60-7.52(2H，m)；7.33-7.27(2H，m)；3.68，3.52(1H?each，ABq，J＝14.7Hz)；1.33(3H，s).
Embodiment 5
Prepare by commercial N-Boc-4-piperidone by the method for describing among the embodiment 3.
Figure A0281004100871
m/z?437(MH+)MW.435.89
m/z?432(MH+)MW.431.47
Figure A0281004100881
m/z?416(MH+)MW.415.47
m/z?420(MH+)MW.419.43
Figure A0281004100883
m/z?427(MH+)MW.426.45
Embodiment 6
5-(2-{[4-(4 '-fluorine [1,1 '-xenyl]-the 4-yl)-the 1-piperazinyl] alkylsulfonyl } ethyl)-2,4-imidazolidine two Ketone
Figure A0281004100884
To 1-(4-fluorophenyl)-phenylpiperazine (0.125mg, 0.48mmol) in the solution of 5ml methylene dichloride, add triethylamine (0.06ml, 0.5mmol) and 2-(2,5-dioxo-4-imidazolidyl)-and 1-ethanesulfonyl chloride (0.113ml 0.48mol). this mixture was stirred 18 hours, be diluted to 25ml with DCM, with also drying, evaporation, crystallization (EtOH-dioxane) of the saturated NaHCO3 of 1N HCl (5ml) (5ml) washing.
LC-MS(APCI)m/z?446.9(MH+).
1H?NMR?δ1.95m(1H)；2.1m(1.15H)，3.2m(13.3H)，4.1m(1H)，7.05d(2H)，7.25d(2.1H)，7.65d(2.2H)，7.80d(1.8H)，8.0bs(NH).
By being prepared as follows initial substance:
2-(2,5-dioxo-4-imidazolidyl)-1-ethanesulfonyl chloride
(2-{[2-(2 to the 5-in the three-necked flask in the ice bath of being placed on that gas inlet pipe, thermometer and short reflux exchanger are being housed, 5-dioxo-4-imidazolidyl) ethyl] disulfide group (disulfanyl) } ethyl)-2,4-imidazolidimedione (6.9mol) is in the suspension of the mixture of 25ml AcOH and 2ml water, under vigorous stirring, under top temperature+5 ℃, blast chlorine 15 minutes (until all resolution of precipitates).Stir them more than 15 minutes then, be evaporated to very small volume (30 ℃ of top temperatures) in a vacuum, be dissolved in the 50ml methylene dichloride, with the careful jolting of saturated NaHCO3 (about 25ml), then with 10% Sulfothiorine jolting, drying, evaporation, with the crystallization of THF-hexane (Lora-Tamayo, M.et al, 1968, An.Quim. 64 (6): 591-606);
1H?NMR：δ2.55m(1.1H)，2.65m(1.8H)，2.70m(1H)，4.55m(1H)。
5-(2-{[2-(2,5-dioxo-4-imidazolidyl) ethyl] disulfide group (disulfanyl) } ethyl)-2, the 4-imidazolidimedione
Be suspended in the high light propylhomoserin of commercial RS (0.18mol) in the 25ml water and add potassium cyanate 1.5g (0.2mol), this mixture was stirred 45 minutes down at 100 ℃, then its part cooling is also once added 10%HCl, this mixture was stirred under 100 ℃ 50 minutes once more.Put it in the refrigerator and spend the night.With crystal filter, water washs in proper order and dry in a vacuum.
LC-MS(APCI)m/z?319.1(MH+).
Provide general generally reaction process below:
Figure A0281004100901
Embodiment 7
(5R)-and the 5-{[(4-phenyl-peiperazinyl) alkylsulfonyl] methyl }-2, the 4-imidazolidimedione
According to the flow preparation title compound that provides among the embodiment 6.
To R-(2,5-dioxo-4-imidazolidyl) methane sulfonyl chloride (100mg, 0.47mmol) in the solution of 2.5mlTHF, by syringe once add the 1-phenylpiperazine (85mg, 0.52mmol) and the 65ul triethylamine (0.52mmol) in 2.5ml THF.This mixture was stirred 3 hours, and the chlorination three second ammoniums of filtering-depositing are with two small portion THF washing, evaporation and with EtOH and AcOH recrystallization on a small quantity.
LC-MS(APCI)m/z?339.1(MH+).
1H?NMR?δ2.5m(2H)，3.1bs(6.5H)，3.3m(2.5H)，4.55m(1H)，6.8t(1H)，6.9d(1.88H)，7.2t(2.05H)，9.1bs(1.7H).
Starting raw material is by being prepared as follows:
R-(2,5-dioxo-4-imidazolidyl) methane sulfonyl chloride
To the R-5-({ [(2 in the three-necked flask in the ice bath of being placed on that gas inlet pipe, thermometer and short reflux exchanger are being housed, 5-dioxo-4-imidazolidyl) methyl] disulfide group (disulfanyl) } ethyl)-2,4-imidazolidimedione (6.9mol) is in the suspension of the mixture of 25ml AcOH and 2ml water, under vigorous stirring, under top temperature+5 ℃, blast chlorine 15 minutes (until all resolution of precipitates).Stir them more than 15 minutes then, be evaporated to very small volume (30 ℃ of top temperatures) in a vacuum, be dissolved in the 50ml methylene dichloride, with the careful jolting of saturated NaHCO3 (about 25ml), then with 10% Sulfothiorine jolting, drying, evaporation, with the crystallization of THF-hexane (Lora-Tamayo, M.et al, 1968, An.Quim. 64 (6): 591-606);
1H?NMR(DMSO-d 6)：δ3.21m(1.1H)，3.3m(0.7H).4,65m(1H).
R-5-({ [(2,5-dioxo-4-imidazolidyl) methyl] disulfide group (disulfanyl) } methyl)-2, the 4-imidazolidimedione
Commercial R Gelucystine (0.18mol) is suspended in the 25ml water, and adds potassium cyanate 1.5g (0.2mol), this mixture is stirred 45min down at 100 ℃.Then its part cooling is also once added 10%HCl, this mixture was stirred under 100 ℃ 50 minutes once more.Put it in the refrigerator and spend the night.With crystal filter, water washs in proper order and dry in a vacuum.
LC-MS(APCI)m/z?291(MH+).
Embodiment 8
(5S)-and the 5-{[(4-phenyl-peiperazinyl) alkylsulfonyl] methyl }-2, the 4-imidazolidimedione
According to the flow preparation title compound that provides among the embodiment 6.
To S-(2,5-dioxo-4-imidazolidyl) methane sulfonyl chloride (100mg, 0.47mmol) in the solution in 2.5mlTHF, by syringe once add the 1-phenylpiperazine (85mg, 0.52mmol) and the solution of 65ul of triethylamine (0.52mmol) in 2.5ml THF.With this mixture stir 3 hours, with sedimentary chlorination three second ammoniums filter, with two small portion THF washing, evaporation and with EtOH and AcOH recrystallization on a small quantity.
LC-MS(APCI)m/z?339.1(MH+).
1H?NMR：δ2.5m(2H)，3.1bs(6.5H)，3.3m(2.5H)，4.55m(1H)，6.8t(1H)，6.9d(1.88H)，7.2t(2.05H)，9.1bs(1.7H).
By being prepared as follows initial substance:
S-(2,5-dioxo-4-imidazolidyl) methane sulfonyl chloride
To the S-5-({ [(2 in the three-necked flask in the ice bath of being placed on that gas inlet pipe, thermometer and short reflux exchanger are being housed, 5-dioxo-4-imidazolidyl) methyl] disulfide group (disulfanyl) } methyl)-2,4-imidazolidimedione (6.9mol) is in the suspension of the mixture of 25ml AcOH and 2ml water, under vigorous stirring, under top temperature+5 ℃, blast chlorine 15 minutes (until all resolution of precipitates).Stir them more than 15 minutes then, be evaporated to very small volume (30 ℃ of top temperatures) in a vacuum, be dissolved in the 50ml methylene dichloride, with the careful jolting of saturated NaHCO3 (about 25ml), then with 10% Sulfothiorine jolting, drying, evaporation, with the crystallization of THF-hexane.(Lora-Tamayo，M.et?al，1968，An.Quim.， 64(6)：591-606)；
1H?NMR(DMSO-d 6)：δ3.2m(0.9H，3.35m(0.9H)，4.50m(1H).
S-5-({ [(2,5-dioxo-4-imidazolidyl) methyl] disulfide group (disulfanyl) } methyl)-2, the 4-imidazolidimedione
Commercial S Gelucystine is suspended in (0.18mol) is suspended in the 25ml water, and add potassium cyanate 1.5g (0.2mol), this mixture is stirred 45min down at 100 ℃.Then its part cooling is also once added 10%HCl, this mixture was stirred under 100 ℃ 50 minutes once more.Put it in the refrigerator and spend the night.With crystal filter, water washs in proper order and dry in a vacuum.
LC-MS(APCI)m/z?291.1(MH+).
Embodiment 9
(R)-5-(([4-(4 '-fluorine [1,1 '-xenyl]-the 4-yl)-the 1-piperazinyl] alkylsulfonyl) methyl)-2, the 4-imidazolidine Diketone
Will be [(R)-2,5-dioxo alkyl imidazole base] methane sulfonyl chloride (0.0127g, 0.060mmol), 1-(4 '-fluorine [1,1 '-xenyl]-the 4-yl) piperazine (0.0154g, 0.060mmol), triethylamine (0.0084mL, 0.060mmol) and exsiccant tetrahydrofuran (THF) (0.70mL) at room temperature stir and spend the night.(0.025g 0.030mmol) also spends the night this mixture jolting to add the polystyrene methyl isocyanate.White suspension carefully is transferred in the round-bottomed flask, and (2 * 1mL) clean, and washings is transferred in the suspension large volume with tetrahydrofuran (THF) with resin.With solvent evaporation, white solid is suspended in the water (5mL), (2 * 1mL) washings, suction filtration is extremely anhydrous, and spends the night 45 ℃ of following vacuum-dryings, obtains about 0.010g title compound for collection on strainer, water.
LC-MS(APCI)m/z?434(MH+).
1H NMR (DMSO-d 6) δ 10.8 (1H, bs), 7.98 (1H, d, J=2Hz), 7.63 (2H, dd, J 1=5Hz, J 2=9Hz), 7.53 (2H, d, J=9Hz), 7.23 (2H, t, J=9Hz), 7.05 (2H, d, J=9Hz), 4.45 (1H, ddd, J 1=2Hz, J 2=4Hz, J 3=6Hz), 3.51 (1H, dd, J 1=15Hz, J 2=7Hz), 3.44 (1H, dd, J 1=15Hz, J 2=4Hz), 3.35-3.25 (8H, m ' s; Because of the water signal fogs) ppm.
13C?NMR(DMSO-d 6)δ173.7，161.3(d，J＝243Hz)，157.3，149.8，136.4(d，J＝3Hz)，130.1，127.7(d，J＝8Hz)，127.2，116.2，115.5(d，J＝21Hz)，53.4，49.4，48.0，44.9.
By being prepared as follows initial substance:
[(R)-2,5-dioxo alkyl imidazole base] methane sulfonyl chloride is according to Mosher et al, 1958, J.Org.Chem 23: 1257. preparations.
1-(4 '-fluorine [1,1 '-xenyl]-the 4-yl) piperazine
With 4-bromo-4 '-fluorine biphenyl (4.46g, 17.8mmol), N-tert-butoxycarbonyl piperazine (3.97g, 21.3mmol), sodium tert-butoxide (2.39g, 24.9mmol), racemize 2,2 '-two (diphenylphosphine)-1,1 '-dinaphthalene (rac-BINAP) (0.082g, 0.131mmol), two-(dibenzyl acetone) palladium (0) (0.041g, 0.045mmol) and dry toluene (45mL) under nitrogen atmosphere, stirring 6 hours under 80 ℃.Should be warm mixture filter, with the warm toluene wash of solid, the mixture that this is warm filters, and solid is with warm toluene wash, and concentrated in a vacuum with filtrate, obtains orange-red crude product, and it was stirred two hours with ether (50mL).Leach solid, with the washing of a small amount of ether, and in a vacuum 45 ℃ of following dried overnight, obtain 5.57g (88% yield) 4-(4 '-fluorine [1,1 '-xenyl]-4-yl)-1-piperazine carboxylic acid tert-butyl ester.This product is dissolved in the dioxane (150mL), and stirs under RT with 4M hydrochloric acid (8.1mL) and to spend the night.Add concentrated hydrochloric acid, and 45 ℃ of following continuously stirring 1.5 hours with 60 ℃ of following continuously stirring 1 hour.With this solution concentration to dry and with solid with ether (100mL) grind, filter, with the ether washing of small volume very and under 45 ℃ drying two hours in a vacuum, obtain 5.26g (103% yield) 1-(4 '-fluorine [1,1 '-xenyl]-the 4-yl) the piperazine dihydrochloride, be light yellow salt.
LC-MS(APCI)m/z?257(MH+).
1H?NMR(DMSO-d 6)δ9.40(2H，bs)，7.64(2H，dd，J 1＝6Hz，J 2＝9Hz)，7.55(2H，d，J＝9Hz)，7.24(2H，t，J＝9Hz)，7.07(2H，d，J＝9Hz)，3.46-3.41(4H，m)，3.25-3.17(4H，m).
This salt is handled with aqueous sodium hydroxide solution, and alkali is sucked in the methylene dichloride.Use Na 2SO 4Drying, filtration and concentrated organic phase obtain title compound, are pale solid.
1H?NMR(DMSO-d 6)δ7.61(2H，dd，J 1＝6Hz，J 2＝9Hz)，7.49(2H，d，J＝9Hz)，7.22(2H，t，J＝9Hz)，6.98(2H，d，J＝9Hz)，3.10-3.06(4H，m)，2.86-2.81(4H，m).
Embodiment 10
The similar technology of describing among use and the embodiment 9 is handled [(4R)-2,5-dioxo alkyl imidazole base] methane sulfonyl chloride with suitable uncle or secondary amine, obtain compound given below.All amine that use all are commercial.
Figure A0281004100941
Following table provides the amido of each compound of said structure.
Embodiment 11
(S)-5-(([4-(4 '-fluorine [1,1 '-xenyl]-the 4-yl)-the 1-piperazinyl] alkylsulfonyl) methyl)-2, the 4-imidazolidine Diketone
Figure A0281004100952
Will be [(S)-2,5-dioxo alkyl imidazole base] methane sulfonyl chloride (0.0127g, 0.060mmol), 1-(4 '-fluorine [1,1 '-xenyl]-the 4-yl) piperazine (0.0154g, 0.060mmol), triethylamine (0.0084mL, 0.060mmol) and exsiccant tetrahydrofuran (THF) (0.70mL) at room temperature stir and spend the night.(0.025g 0.030mmol) also spends the night this mixture jolting to add the polystyrene methyl isocyanate.White suspension carefully is transferred in the round-bottomed flask, and (2 * 1mL) clean, and washings is transferred in the suspension large volume with tetrahydrofuran (THF) with resin.With solvent evaporation, white solid is suspended in the water (5mL), (2 * 1mL) washings, suction filtration is extremely anhydrous, and spends the night 45 ℃ of following vacuum-dryings, obtains about 0.010g title compound for collection on strainer, water.
LC-MS(APCI)m/z?433(MH+).
1H NMR (DMSO-d 6) δ 10.8 (1H, br s), 7.98 (1H, d, J=2Hz), 7.63 (2H, dd, J 1=5Hz, J 2=9Hz), 7.53 (2H, d, J=9Hz), 7.23 (2H, t, J=9Hz), 7.05 (2H, d, J=9Hz), 4.45 (1H, ddd, J 1=2Hz, J 2=4Hz, J 3=6Hz), 3.51 (1H, dd, J 1=15Hz, J 2=7Hz), 3.44 (1H, dd, J 1=15Hz, J 2=4Hz), 3.35-3.25 (8H, m ' s; Because of the water signal fogs).
13C?NMR(DMSO-d 6)δ173.7，161.3(d，J＝243Hz)，157.3，149.8，136.4(d，J＝3Hz)，130.1，127.7(d，J＝8Hz)，127.2，116.2，115.5(d，J＝21Hz)，53.4，49.4，48.0，44.9.
By being prepared as follows initial substance:
According to Mosher et al, 1958, J.Org.Chem 23: 1257 preparation [(S)-2,5-dioxo alkyl imidazole base] methane sulfonyl chlorides.
According to embodiment 9 preparation 1-(4 '-fluorine [1,1 '-xenyl]-4-yl) piperazine.
Embodiment 12
The similar technology of describing among use and the embodiment 11 with [(4S)-2,5-dioxo alkyl imidazole base] methane sulfonyl chloride and suitable uncle or secondary amine reaction, obtains following title compound.The amine that uses all is commercial.
Figure A0281004100961
Following table provides the amido of each compound of said structure
Figure A0281004100962
Figure A0281004100971
Embodiment 13
Synthetic glycolylurea (wherein E is carbon or heteroatoms) with following general structure:
Representational synthetic route:
(5R, S)-5-[4-(4-fluoro-phenyl)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2, the 4-diketone.
Figure A0281004100973
Reagent: a) MeSO 2Cl, DCM, 0 ℃, 2.5h.b) i.LHMDS, THF, 45min.ii.MeOAc, THF, 40min.c) KCN, (NH 4) 2CO 3, 50%EtOH/H 2O, 70 ℃, 17h.
The sulphonamide intermediate
(1): for the NMR-data, referring to experimental section.
4-(4-fluoro-phenyl)-1-methane sulfonyl-piperidines
With 4-(4-fluoro-phenyl) piperidine hydrochlorate (2.16g; 10mmol) and diisopropyl ethyl amine (4.35ml; 25mmol) be dissolved among the DCM (60ml), and under nitrogen, in ice/water-bath, cool off.With methane sulfonyl chloride (1.56ml; 10.1mmol) be dissolved among the DCM (5ml) and in 2 minutes and be added dropwise to.This reaction mixture is stirred 2.5h in ice/water-bath.With this reaction mixture with rare HCl (aq), pH=2, H 2O, and 1MNa 2CO 3The lime carbonate washing.With organic phase drying (Na 2SO 4), filter and evaporation, obtain thick product, it is used THF/ normal hexane recrystallization.By filtration taking-up clear crystal and 45 ℃ of following vacuum-dryings.
Obtain 1.96g (76% yield) title compound.
LC-MS(APCI)m/z?258(MH+).
1H?NMR(DMSO-d 6)：δ7.31(m，2H)，7.12(m，2H)，3.67(m，2H)，2.80(dt，2H)，2.64(m，1H)，1.85(m，2H)，1.65(m，2H).
5-chloro-2-(1-methane sulfonyl-piperidin-4-yl oxygen base)-pyridine
Prepare title compound according to the description in synthetic 4-(4-fluoro-phenyl)-1-methane sulfonyl-piperidines.5-chloro-2-(piperidin-4-yl oxygen base)-pyridine (2.13g; 10mmol) (preparation of this compound is carried out according to the description among the WO99-GB2801), diisopropyl ethyl amine (2.20ml; 12.5mmol) and methane sulfonyl chloride (1.56ml; 10.1mmol) obtain 2.14g (74%) title compound.
LC-MS(APCI)m/z?291(MH+).
1H?NMR(DMSO-d 6)：δ8.20(d，1H)，7.81(dd，1H)，6.87(d，1H)，5.09(m，1H)，3.41-3.30(m，2H)，3.15-3.06(m，2H)，2.90(s，3H)，2.04(m，2H)，1.75(m，2H).
1-(methyl sulphonyl)-4-[5-(trifluoromethyl) pyridine-2-yl] piperazine
With 1-[5-(trifluoromethyl)-pyridine-2-yl]-piperazine (1.0g; 4.3mmol) and diisopropyl ethyl amine (0.9ml; 5.4mmol) be dissolved among the DCM (10ml).Add molecular sieve and solution is cooled off in ice/water-bath.Add methane sulfonyl chlorine (0.9ml; 12mmol) and with the slurry that forms stirred 15 minutes, make this reaction mixture reach room temperature and after 1 hour, by adding 5%KHCO 3Make the reaction cancellation.Evaporating solvent also is dissolved in DCM and 5%KHCO with resistates 3Between.Separate and aqueous phase extracted with DCM (1x).With the organic phase drying (MgSO that merges 4), filter and evaporation, obtain thick product, be light yellow solid.
With EtOAc/Heptan recrystallization (3x), obtain title compound, be clear crystal.
Obtain 1.06g (79% yield) title compound.
Purity＞95% (HPLC, 254nm)
LC-MS(APCI)m/z?310(MH+).
1H-NMR(DMSO-d 6)：δ8.44(1H，bs)，7.85(1H，dd)，7.02(1H，d)，3.77(4H，bt)，3.20(4H，bt)，2.90(3H，s).
Below compound by synthetic 1-(methyl sulphonyl)-4-[5-(trifluoromethyl) pyridine-2-yl] description in the piperazine carries out.
6-[4-(methyl sulphonyl) piperazine-1-yl] pyridine-3-nitrile
6-in DCM (20ml) (1-piperazine)-pyridine-3-nitrile (carbonitrile) (2.07g; 11mmol), diisopropyl ethyl amine (2.4ml; 13.8mmol) and methane sulfonyl chlorine (0.86ml; 11mmol) obtain 2.53g (86%) title compound.
Purity＞95% (NMR).
LC-MS(APCI)m/z?267(MH+).
1H-NMR(DMSO-d 6)：δ8.52(1H，dd)，7.90(1H，dd)，7.00(1H，d)，3.79(4H，brt)，3.19(4H，bt)，2.90(3H，s).
1-(4-fluorophenyl)-4-(methyl sulphonyl) piperazine
1-in DCM (20ml) (4-fluorophenyl)-piperazine (1.98g; 11mmol), diisopropyl ethyl amine (2.4ml; 13.8mmol) and methane sulfonyl chlorine (0.86ml; 11mmol), obtain 2.46g (86%) title compound.
Purity＞95% (NMR).
LC-MS(APCI)m/z?259(MH+).
1H-NMR(DMSO-d 6)：δ7.11-6.96(4H，m)，3.28-3.20(4H，m)，3.20-3.14(4H，m)，2.92(3H，s).
1-[(4-is fluorine-based) methyl]-4-(methyl sulphonyl) piperazine
1-in DCM (20ml) (4-luorobenzyl)-piperazine (2.14g; 11mmol), diisopropyl ethyl amine (2.4ml; 13.8mmol) and methane sulfonyl chlorine (0.86ml; 11mmol), obtain 1.97g (65%) title compound.
Purity＞95% (NMR)
LC-MS(APCI)m/z?273(MH+).
1H-NMR(DMSO-d 6)：δ7.40-7.28(2H，m)，7.21-7.10(2H，m)，3.50(2H，bs)，3.10(4H，m)，2.87(3H，bs)，2.44(4H，m).
2-[4-(methyl sulphonyl) piperazine-1-yl] pyrimidine
With 1-(2-pyrimidyl)-piperazine dihydrochloride (2.61g; 11mmol) and diisopropyl ethyl amine (7.2ml; 41.3mmol) stirring 30min in DCM (20ml).With sedimentary salt by removing by filter and, resistates being dissolved among the DCM (20ml) again with solvent evaporation.Add diisopropyl ethyl amine (2.4ml; 11mmol) and the 4A molecular sieve, yellow solution is cooled off in ice/water-bath and add methane sulfonyl chlorine (0.86ml; 11mmol).The gained red solution was stirred 15 minutes, make this reaction mixture reach room temperature and after 1 hour, by adding 5%KHCO 3Make the reaction cancellation.Evaporating solvent also is dissolved in DCM and 5%KHCO with resistates 3Between.Make separation difficulty because of forming foam.With water with NaCl saturated and with pH regulator to 10-11.With EtOAc extraction (3x).With the organic phase drying (MgSO that merges 4), filter and evaporation, obtain thick product, be red powder.
Obtain 0.6g (22%) title compound.
Purity＞95% (NMR).
LC-MS(APCI)m/z?243(MH+).
1H-NMR(DMSO-d 6)：δ8.39(2H，d)，6.68(1H，t)，3.85(4H，bt)，3.17(4H，bt)，2.88(3H，s).
4-(4-chloro-phenyl-)-1-(methyl sulphonyl) piperidines
Prepare title compound by the description in synthetic 4-(4-fluoro-phenyl)-1-methane sulfonyl-piperidines.
4-in DCM (30ml) (4-chloro-phenyl-) piperidine hydrochlorate (0.9g; 3.9mmol), (1.7ml is 9.7mmol) with methane sulfonyl chlorine (0.33ml for diisopropyl ethyl amine; 4.3mmol), after with EtOAc/ heptane recrystallization, obtain 0.82g (78%) title compound.
Purity＞95%.
LC-MS(APCI)m/z?274(MH+)。
1H?NMR?CDCl 3：δ1.83(2H，dd)；1.92-2.01(2H，m)；2.55-2.68(1H，m)；2.79(2H，dt)；2.85(3H，s)；3.97(2H，d)；7.16(2H，d)；7.32(2H，d).
The ester intermediate
All other esters that use are commercial or above-described.
4-pyrimidine-2-base-ethyl butyrate
With 2-bromo pyrimi piperidine (1.0g, 6.3mmol) slurryization in dry THF (8mL).Blast N by slurry 2(g) 5min.Power is gone into Pd (CH 3CN) 2Cl 2(8mg, 0.03mmol) and PPh 3(23.6mg, 0.09mmol).Under nitrogen atmosphere by a part add 4-oxyethyl group-4-oxo-butyl zinc bromide (0.5M/THF) (15mL, 7.5mL).The gained brown solution is at room temperature stirred 2h.Add H 2O (5mL) also stirs 60min with mixture, then evaporating solvent.Be dissolved in resistates among the DCM (150mL) again and usefulness 0.5M trisodium citrate (100mL), H 2O (100mL) and salt solution (100mL) washing, dry (MgSO 4), filter and evaporation, obtain the 1.3g orange oil.With thick product with 100% heptane to EtOAc as elutriant purifying on 70g Si-60 silica gel.Collect should the part of product and with solvent evaporation obtains yellow oil.Purity (analyzing by NMR)＞95% is considered to be enough to satisfy our needs.Obtain 1.12g (92% yield) title compound.
LC-MS(APCI)m/z?195(MH+).
1H-NMR(CDCl 3)：δ8.67(d，2H)，7.14(t，1H)，4.12(q，2H)，3.02(t，2H)，2.41(t，2H)，2.18(q，2H)，1.25(t，3H).
3-pyrimidine-2-base-ethyl propionate
(1.0g 6.3mmol) is dissolved among the THF (8mL) and blasts nitrogen with the 2-bromo pyrimi piperidine.Add Pd (MeCN) 2Cl 2(8mg, 0.03mmol) and PPh 3(23.6mg, 0.09mmol), then add 3-oxyethyl group-3-oxopropyl bromide (3-oxyethyl group-3-oxopropyl zinkbromid) (15mL, 7.5mmol).Should react and at room temperature stir a couple of days.Should be thick product with heptane-EtOAC 3: 1 as elutriant purifying on silica gel, obtain 0.60g (52%) title compound.
LC-MS(APCI)m/z?181(MH+).
4-(2-methoxyl group-2-oxoethyl) piperidines-1-carboxylic acid tert-butyl ester
With 4-(2-methoxyl group-2-oxo ethylidene) piperidines-1-carboxylic acid tert-butyl ester (3.6g, 14mmol) and the wetting 10%Pd/C of water (0.8g) in MeOH (75mL), mix and be incorporated in H 2(1atm) stir 4h down.This mixture by Celite and concentrated, is obtained title compound (3.6g, 99%).
LC-MS(APCI)m/z?158(MH+-boc).
1H?NMR(CDCl 3)：4.07(2H，bs)；3.68(3H，s)；2.72(2H，t)；2.25(2H，d，J＝7.1Hz)；2.01-1.86(1H，m)；1.68(2H，d)；1.46(9H，s)；1.23-1.08(2H，m).
The ketone intermediate
Figure A0281004101041
(1): thick product, do not obtain NMR, mtrl. is directly used in following synthesis step.
1-[4-4 (fluoro-phenyl)-piperidines-1-alkylsulfonyl]-third-2-ketone
With 4-(4-fluoro-phenyl)-1-methane sulfonyl-piperidines (100mg; 0.39mmol) under the protection nitrogen atmosphere, be dissolved in the dry THF (3mL).At room temperature add two (trimethyl silyl) lithiumbromide (with the 1.0M solution form in THF) (1.0mL by a part; 1.0mmol), the gained yellow solution is stirred 45min.Add the methyl acetate (50mg that is dissolved in the dry THF (0.5mL); 0.68mmol), this mixture is at room temperature stirred 40min.This reaction is by adding NH 4(2mL) cancellation of Cl (saturated).Be dissolved in DCM and H with this mixture evaporation and with the gained solid 2In the mixture of O.Separate organic phase and use salt water washing, drying (MgSO 4), filter and evaporation.Thick product is washed on 20g Si-60 silica gel with 1 00% heptane to 50%EtOAc gradient solution, UV=254nm is used for monitoring.To contain the part evaporation of this product, so obtain title compound, be colorless solid.
Obtain 70mg (59% yield).
TLC (Si-60; EtOAc: heptane (2: 1)): R f=0.65
LC-MS(APCI)m/z?300.1(MH+).
1H-NMR(CDCl 3)：δ7.17(m，2H)，7.01(m，2H)，4.02(s，2H)，3.93(m，2H)，2.94(dt，2H)，2.63(m，1H)，2.46(s，3H)，1.91(m，2H)，1.77(m，2H).
Below compound by synthetic 1-[4-4 (fluoro-phenyl)-piperidines-1-alkylsulfonyl]-description preparation in propane-2-ketone.
1-[4-4 (fluoro-phenyl)-piperidines-1-alkylsulfonyl]-4-phenyl-Ding-2-ketone
4-(4-fluoro-phenyl)-1-methane sulfonyl-piperidines (100mg; 0.39mmol), methyl-3-phenylpropionic acid ester (112mg; 0.68mmol) and two (trimethyl silyl) acid amides lithium 1.0M/THF (1.0mL; 1.0mmol), obtain 93mg (61%) title compound.
TLC (Si-60; EtOAc: heptane (2: 1)): R f=0.68
1H-NMR(CDCl 3)：δ7.30-7.10(m，7H)，6.99(m，2H)，3.97(s，2H)，3.79(m，2H)，3.11(t，2H)，2.94(t，2H)，2.83(dt，2H)2.57(m，1H)，1.83(m，2H)，1.70(m，2H).
1-[4-4 (fluoro-phenyl)-piperidines-1-alkylsulfonyl]-5-imidazoles-penta-2-ketone
4-(4-fluoro-phenyl)-1-methane sulfonyl-piperidines (100mg; 0.39mmol), 4-imidazoles-1 base-ethyl butyrate (127mg; 0.70mmol) and two (trimethyl silyl) acid amides lithium 1.0M/THF (1.0mL; 1.0mmol), obtain 75mg (48%) title compound.
LC-MS(APCI)m/z?394(MH+).
1H-NMR(CDCl 3)：δ7.48(s，1H)，7.16(m，2H)，7.08(s，1H)，7.02(m，2H)，6.93(s，2H)，4.00(t，2H)，3.97(s，2H)，3.90(m，2H)，2.92(dt，2H)，2.77(t，2H)，2.63(m，1H)，2.12(q，2H)，1.92(m，2H)，1.77(m，2H).
1-[4-(4-fluoro-phenyl)-piperidines-1-alkylsulfonyl]-5-pyrimidine-2-base-penta-2-ketone
With 4-(4-fluoro-phenyl)-1-methane sulfonyl-piperidines (150mg; 0.39mmol) be dissolved among the exsiccant THF (3mL) and on ice/saline mixture, cool off.Add two (trimethyl silyl) acid amides lithium (with the 1.0M solution form in THF) (1.5mL; 1.5mmol), the gained mixture is stirred 45min.Add and be dissolved in 4-pyrimidine-2-base-ethyl butyrate (169mg; 0.87mmol), this mixture is stirred 30min, make it reach room temperature then.After 2h hour, the LC/MS of reaction mixture analyzes transformation efficiency＞98% that shows initial substance and passes through to add saturated NH 4Cl (aq) (2mL) will react cancellation.Be dissolved in DCM and 5%KHCO with this mixture evaporation and with the gained solid 3Mixture in.Evaporate once with DCM with the organic phase separation and with water.Organic with what merge to using salt water washing, drying (MgSO 4), filter, and evaporation obtains yellow oil.Be dissolved in oil among the EtOAc and add isohexane until forming solid.Evaporating solvent obtains yellow thick product.This material is only analyzed with LC/MS, and is used for next step under not being further purified.
Obtain the thick title compound of 234mg.
LC-MS(APCI)m/z?406.1(MH+).
Below compound by synthetic 1-[4-(4-fluoro-phenyl)-piperidines-1-alkylsulfonyl]-description preparation in 5-pyrimidine-2-base penta-2-ketone.They obtain with thick product and be not further purified use down.
1-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl]-third-2-ketone
By 5-chloro-2-(1-methane sulfonyl-piperidin-4-yl oxygen base)-pyridine (150mg; 0.51mmol), methyl acetate (61mg; 0.82mmol) and two (trimethyl silyl) acid amides lithium 1.0M/THF (1.3ml; 1.3mmol) initial.
Obtain the thick title compound of 161mg of.Be not further purified use down.
LC-MS(APCI)m/z?333.1(MH+).
1-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl]-4-phenyl-Ding-2-ketone
By 5-chloro-2-(1-methane sulfonyl-piperidin-4-yl oxygen base)-pyridine (150mg; 0.51mmol), methyl-3-phenylpropionic acid ester (126mg; 0.77mmol) and two (trimethyl silyl) acid amides lithium 1.0M/THF (1.3ml; 1.3mmol) initial.
Obtain the thick title compound of 258mg.Be not further purified use down.
LC-MS(APCI)m/z?423.2(MH+).
1-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl]-5-imidazoles-1-base-penta-2-ketone
By 5-chloro-2-(1-methane sulfonyl-piperidin-4-yl oxygen base)-pyridine (150mg; 0.51mmol), 4-imidazoles-1-base-ethyl butyrate (140mg; 0.77mmol) and two (trimethyl silyl) acid amides lithium 1.0M/THF (1.3ml; 1.3mmol) initial.
Obtain the thick title compound of 268mg.Be not further purified use down.
LC-MS(APCI)m/z?427.2(MH+).
1-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl]-5-pyrimidine-2-base-penta-2-ketone
By 5-chloro-2-(1-methane sulfonyl-piperidin-4-yl oxygen base)-pyridine (150mg; 0.51mmol), 4-pyrimidine-2-base-ethyl butyrate (147mg; 0.76mmol) and two (trimethyl silyl) acid amides lithium 1.0M/THF (1.3ml; 1.3mmol) initial.
Obtain the thick title compound of 244mg.Be not further purified use down.
LC-MS(APCI)m/z?439.2(MH+).
1-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl]-Ding-2-ketone
LC-MS(APCI)m/z?347(MH+)
1-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl]-penta-2-ketone
LC-MS(APCI)m/z?361(MH+)
1-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl]-4-methyl-penta-2-ketone
LC-MS(APCI)m/z?375(MH+)
1-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl]-4-pyrimidine-2-base-Ding-2-ketone
LC-MS(APCI)m/z?425(MH+)
1-(4-[(5-chloropyridine-2-yl) and the oxygen base] piperidines-1-yl } alkylsulfonyl)-3-(3-aminomethyl phenyl) third-2-ketone
LC-MS(APCI)m/z?423(MH+)
1-(4-[(5-chloropyridine-2-yl) and the oxygen base] piperidines-1-yl } alkylsulfonyl)-3-tetrahydrochysene-2H-pyrans-4-base third-2-ketone
LC-MS(APCI)m/z?417(MH+)
1-(4-[(5-chloropyridine-2-yl) and the oxygen base] piperidines-1-yl } alkylsulfonyl)-5-morpholine-4-base penta-2-ketone
LC-MS(APCI)m/z?446(MH+)
5-(4-[(5-chloropyridine-2-yl) and the oxygen base] piperidines-1-yl } alkylsulfonyl)-4-oxo valeronitrile
LC-MS(APCI)m/z?372(MH+)
5-(4-[(5-chloropyridine-2-yl) and the oxygen base] piperidines-1-yl } alkylsulfonyl)-4-oxo amyl group carboxylamine 1,1-dimethyl ethyl ester
LC-MS(APCI)m/z?476(MH+)
1-(4-[(5-chloropyridine-2-yl) and the oxygen base] piperidines-1-yl } alkylsulfonyl)-4-morpholine-4-Ji Ding-2-ketone
LC-MS(APCI)m/z?432(MH+)
2-(4-[(5-chloropyridine-2-yl) and the oxygen base] piperidines-1-yl } alkylsulfonyl)-1-phenyl ethyl ketone
LC-MS(APCI)m/z?395(MH+)
2-(4-[(5-chloropyridine-2-yl) and the oxygen base] piperidines-1-yl } alkylsulfonyl)-1-(4-fluorophenyl) ethyl ketone
LC-MS(APCI)m/z?413(MH+)
2-(4-[(5-chloropyridine-2-yl) and the oxygen base] piperidines-1-yl } alkylsulfonyl)-1-(1H-imidazol-4 yl) ethyl ketone
LC-MS(APCI)m/z?385(MH+)
4-[({4-[(5-chloropyridine-2-yl) oxygen base] piperidines-1-yl } alkylsulfonyl) ethanoyl] benzamide
n.d.
1-(4-[(5-chloropyridine-2-yl) and the oxygen base] piperidines-1-yl } alkylsulfonyl)-4-(1H-1,2,4-triazol-1-yl) fourth-2-ketone
LC-MS(APCI)m/z?414(MH+)
1-{[4-(4-fluorophenyl) piperidines-1-yl] alkylsulfonyl }-4-pyrimidine-2-base fourth-2-ketone
LC-MS(APCI)m/z?392(MH+)
1-{[4-(4-fluorophenyl) piperidines-1-yl] alkylsulfonyl }-3-tetrahydrochysene-2H-pyrans-4-base third-2-ketone
LC-MS(APCI)m/z?384(MH+)
4-({ [4-(4-fluorophenyl) piperidines-1-yl] alkylsulfonyl } ethanoyl) benzamide
LC-MS(APCI)m/z?405(MH+)
2-{[4-(4-fluorophenyl) piperidines-1-yl] alkylsulfonyl }-1-(1H-imidazol-4 yl) ethyl ketone
LC-MS(APCI)m/z?352(MH+)
1-{[4-(4-chloro-phenyl-) piperidines-1-yl] alkylsulfonyl }-3-tetrahydrochysene-2H-pyrans-4-base third-2-ketone
LC-MS(APCI)m/z?400(MH+)
1-{[4-(4-chloro-phenyl-) piperidines-1-yl] alkylsulfonyl }-5-morpholine-4-base penta-2-ketone
LC-MS(APCI)m/z?429(MH+)
1-(4-[5-(trifluoromethyl) pyridine-2-yl] and piperazine-1-yl } alkylsulfonyl) third-2-ketone
LC-MS(APCI)m/z?352.1(MH+)
The 6-{4-[(2-oxopropyl) alkylsulfonyl] piperazine-1-yl } pyridine-3-nitrile
LC-MS(APCI)m/z?309.1(MH+)
1-{[4-(4-fluorophenyl) piperazine-1-yl] alkylsulfonyl } third-2-ketone
LC-MS(APCI)m/z?301.1(MH+)
1-(the 4-[(4-fluorophenyl) and methyl] piperazine-1-yl } alkylsulfonyl) third-2-ketone
LC-MS(APCI)m/z?315.1(MH+)
1-[(4-pyrimidine-2-base piperazine-1-yl) alkylsulfonyl] third-2-ketone
LC-MS(APCI)m/z?285.1(MH+)
4-[3-(4-[(5-chloropyridine-2-yl) and the oxygen base] piperidines-1-yl } alkylsulfonyl)-the 2-oxopropyl] piperidines-1-carboxylic acid 1,1-dimethyl ethyl ester
LC-MS(APCI)m/z?517(MH+).
The glycolylurea of general formula I I
Figure A0281004101101
Figure A0281004101102
Figure A0281004101111
Figure A0281004101121
(1): NMR can obtain, referring to experimental section
(2): purifying not.
(5R, S)-5-[4-(4-fluoro-phenyl)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2, the 4-diketone
With 1-[4-4 (fluorophenyl)-piperidines-1-alkylsulfonyl]-third-2-ketone (68mg; 0.23mmol), KCN (30mg; 0.46mmol) and (NH 4) 2CO 3(111mg; 1.16mmol) be suspended in the 50%EtOH/H that is sealed in the 22ml sealed tube 2Among the O (8mL) and be heated to 70 ℃, form solution.This mixture is stirred 17h down at 70 ℃.In pipe, form solid, this mixture is cooled to room temperature and, resistates is suspended in the water usefulness 1.0M HCl adjusting pH to pH=6 with solvent evaporation.Water is extracted with MeCN.Solid matter is merged and evaporation.With thick product with partly preparing the HPLC system and the C-18 pillar (is used MeCN/H 2O+0.1%TFA is as elutriant) purifying.The part merga pass evaporation that will contain product removes desolvates, and obtains title compound, is colorless solid
Obtain 53mg (62% yield).
Purity (measuring)＞98% by NMR
LC-MS(APCI)m/z?370.0(MH+).
1H-NMR(DMSO-d 6)：δ10.74(s，1H)，8.02(s，1H)，7.31(m，2H)，7.12(m，2H)，3.61(m，2H)，3.51(d，1H)，3.34(d，1H)，2.86(m，2H)，2.63(m，1H)，1.82(m，2H)，1.63(m，2H)，1.34(s，3H).
(5R, S)-5-[4-(4-fluoro-phenyl)-piperidines-1-alkylsulfonyl methyl]-5-styroyl-imidazolidine-2, the 4-diketone
This title compound according to synthetic (5R, S)-5-[4-(4-fluoro-phenyl)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2, the description preparation in the 4-diketone.
1-[4-4 (fluorophenyl)-piperidines-1-alkylsulfonyl]-4-phenyl-Ding-2-ketone (93mg; 0.24mmol), KCN (40mg; 0.61mmol) and (NH 4) 2CO 3(117mg; 1.22mmol) obtain 37mg (33%) title compound.
LC-MS(APCI)m/z?460.1(MH+).
1H-NMR(DMSO-d 6)：δ10.87(s，1H)，8.13(s，1H)，7.30(m，4H)，7.15(m，5H)，3.63(m，2H)，3.56(d，1H)，3.41(d，1H)，2.87(m，2H)，2.61(m，2H)，2.39(m，1H)，1.92(bt，2H)，1.83(m，2H)，1.63(m，2H).
(5R, S)-5-[4-(4-fluoro-phenyl)-piperidines-1-alkylsulfonyl methyl]-5-(3-imidazoles-1-base-propyl group)-imidazoles Alkane-2, the 4-diketone
1-[4-4 (fluorophenyl)-piperidines-1-alkylsulfonyl]-5-imidazoles-Ding-2-ketone (75mg; 0.19mmol), KCN (30mg; 0.46mmol) and (NH 4) 2CO 3(91mg; 0.95mmol) be dissolved in the EtOH/H that is sealed in the 22mL pipe 2O (1/1) (10mL) in, and stir down 17.5h at 70 ℃.Add another part KCN (40mg; 0.61mmol) and (NH 4) CO 3(250mg; 2.60mmol) and with this mixture at 70 ℃ of following restir 16h.Evaporating solvent also is suspended in H with resistates 2Among the O, filter out sedimentary thick product and with partly preparing the HPLC system and the C-18 pillar (is used MeCN/H 2O+0.1%TFA is as elutriant) purifying.To contain the partial purification of this product and remove MeCN, use 5%KHCO by evaporation 3Acid water is made alkaline pH=8-9, sedimentary product is extracted with EtoAc.With organic phase drying (Na 2SO 4), filter and evaporation, obtain title compound, be colorless solid.
Obtain 60mg (68% yield)
LC-MS(APCI)m/z?464.2(MH+).
1H-NMR(DMSO-d 6)：δ10.75(bs，1H)，8.06(s，1H)，7.59(s，1H)，7.30(m，2H)，7.16-7.08(m，3H)，6.88(s，1H)，3.95(m，2H)，3.60(m，2H)，3.47(d，1H)，3.35(d，1H)，2.86(m，2H)，2.62(m，1H)，1.86-1.50(m，8H).
(5R, S)-5-[4-(4-fluoro-phenyl)-piperidines-1-alkylsulfonyl methyl]-5-(3-pyrimidine-2-base-propyl group)-imidazoles Alkane-2, the 4-diketone
With 1-[4-(4-fluoro-phenyl)-piperidines-1-alkylsulfonyl]-5-pyrimidine-2-base-penta-2-ketone (234mg; Max0.58mmol), KCN (151mg; 2.3mmol) and (NH 4) 2CO 3(557mg; 5.8mmol) was is suspended in the EtOH/H in the 40mL sealed tube 2O (1/1) (26mL) in.With this mixture heating up to 70 ℃, and gained suspension stirred 16h.
LC/MS analyzes demonstration, residual 15% unreacted ketone, and add other Partial K CN (65mg; 1mmol) with (NH 4) 2CO 3(245mg; 2.55mmol), with this mixture heating up to 70 ℃, reheat 16h.Desolvate by evaporating to remove, and with resistates H 2O (25mL) handles.Filter out sedimentary thick product and with partly preparing the HPLC system and the C-18 pillar (is used MeCN/H 2O+0.1%TFA is as elutriant) purifying.To contain the partial purification of this product and remove MeCN, use 5%KHCO by evaporation 3Acid water is made alkaline pH=8-9, filters out sedimentary product, wash with water and under reduced pressure under 40 ℃ in moisture eliminator dried overnight.So obtain title compound, be colorless solid.Purity＞98%byNMR.
Obtain 120mg (43% yield, 2 steps).
LC-MS(APCI)m/z?476.2(MH+).
1H-NMR(DMSO-d 6)：δ10.77(s，1H)，8.72(d，2H)，8.03(s，1H)，7.36-7.27(m，3H)，7.15-7.09(m，2H)，3.60(m，2H)，3.50(d，1H)，3.34(d，1H)，2.92-2.80(m，4H)，2.62(m，1H)，1.86-1.54(m，8H).
Below compound by synthetic (5R, S)-5-[4-(4-fluoro-phenyl)-piperidines-1-alkylsulfonyl methyl]-5-(3-pyrimidine-2-base-propyl group)-imidazolidine-2, the description preparation in the 4-diketone.
(5R, S)-5-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2, The 4-diketone
Do not need purifying, after the reaction mixture evaporation and adding entry, the precipitation product is enough pure, and ((220nm 254nm) analyzes with NMR purity＞98% by HPLC.)
Obtain 147mg (71% yield, 2 steps) title compound, be colorless solid.
LC-MS(APCI)m/z?403.1(MH+).
1H-NMR(DMSO-d 6)：δ10.73(bs，1H)，8.20(d，1H)，8.01(s，1H)，7.81(dd，1H)，6.87(d，1H)，5.09(m，1H)，3.52(d，1H)，3.35(d，1H)，3.42-3.26(m，2H+H 2O)，3.18-3.06(m，2H)，2.08-1.96(m，2H)，1.79-1.65(m，2H)，1.33(s，3H).
(5S)-5-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2,4- Diketone and (5R)-5-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2, The 4-diketone
Corresponding racemize material (74mg) be dissolved among 36mL isohexane/EtOH (25/75) and be separated into pure optically active isomer with following Gilson HPLC system:
Pillar: CHIRALCEL OD, 2.0 * 25cm, flow velocity=6.0mL/min, elutriant=isohexane/EtOH (25/75), temperature=room temperature, detector UV=220nm.
Collect on optically active isomer and the CHIRALCEL OD-H and collect 0.46 * 25cm, 0.5mL/min, isohexane/EtOH (25/75), envrionment temperature, 220nm.
Rt=9.88min.ee＞99% is for very fast wash-out enantiomer, 29mg (39%).
Rt=11.45min.ee=98.7% is for slow wash-out enantiomer, 27mg (36%).
LC-MS(APCI)m/z?403.1(MH+)。
(5R, S)-5-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-5-styroyl-imidazolidine -2, the 4-diketone.
By the initial 1-[4-of thick product (5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl]-4-phenyl-Ding-2-ketone (258mg; Max 0.51mmol).
Purifying crude product carries out on 70g Si-60 gel, uses DCM+5%MeOH as elutriant.Purity＞96% is (by NMR and HPLC (220nm 254nm) analyzes).
Obtain 201mg (80% yield, 2 steps) title compound, be colorless solid.
LC-MS(APCI)m/z?493.0(MH+).
1H-NMR(DMSO-d 6)：δ10.86(bs，1H)，8.21(bd，1H)，8.13(s，1H)，7.81(dd，1H)，7.33-7.24(m，2H)，7.22-7.14(m，3H)，6.87(d，1H)，5.10(m，1H)，3.56(d，1H)，3.42(d，1H)，3.43-3.28(m，2H+H 2O)，3.20-3.08(m，2H)，2.66-2.52(m，1H)，2.45-2.31(m，1H)，2.08-1.96(m，2H)，1.96-1.83(m，2H)，1.81-1.65(m，2H).
(5R, S)-5-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-5-(3-imidazoles-1 base-third Base)-and imidazolidine-2, the 4-diketone
By thick 1-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl]-5-imidazoles-1-base-penta-2-ketone (268mg; Max 0.51mmol) initial.
Obtain 151mg (59% yield, 2 steps) title compound, be colorless solid.
Purity＞98%by NMR.
LC-MS(APCI)m/z?497.2(MH+).
1H-NMR(DMSO-d 6)：δ10.81(bs，1H)，8.20(d，1H)，8.05(s，1H)，7.81(dd，1H)，7.59(bs，1H)，7.13(bs，1H)，6.88(bs，1H)，6.87(d，1H)，5.08(m，1H)，3.47(d，1H)，3.40-3.28(m，3H+H 2O)，3.17-3.06(m，2H)，2.07-1.95(m，2H)，1.79-1.64(m，3H)，1.61-1.48(m，3H).
(5R, S)-5-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-5-(the 3-pyrimidine-2-base- Propyl group)-and imidazolidine-2, the 4-diketone
By thick 1-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl]-5-pyrimidine-2-base-penta-2-ketone (244mg; Max 0.51mmol) initial.
Obtain 105mg (49% yield, 2 steps) title compound, be colorless solid.
Purity＞98%by NMR.
1H-NMR(DMSO-d 6)：δ10.77(bs，1H)，8.72(d，2H)，8.20(d，1H)，8.03(s，1H)，7.81(dd，1H)，7.34(t，1H)，6.87(d，1H)，5.08(m，1H)，3.50(d，1H)，3.41-3.29(m，3H+H 2O)，3.16-3.07(m，2H)，2.83(t，2H)，2.06-1.96(m，2H)，1.81-1.66(m，5H)，1.63-1.51(m，1H).
(5S)-5-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-5-(3-pyrimidine-2-base-third Base)-and imidazolidine-2,4-diketone and (5R)-5-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl first Base]-5-(3-pyrimidine-2-base-propyl group)-imidazolidine-2, the 4-diketone
Corresponding racemize material (40mg) is dissolved in 26mL isohexane/EtOH (25/75); and by with separate 5R; S)-5-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2, the same adjustment that the 4-diketone is described is separated into pure enantiomorph.
Rt=17.6min.ee＞99% is for very fast wash-out enantiomer, 17mg (42%).
Rt=21.0min.ee=98.9% is for slow wash-out enantiomer, 15mg (37%).
LC-MS(APCI)m/z?509(MH+).
5-[({4-[(5-chloropyridine-2-yl) oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-5-ethyl imidazol(e) alkane-2,4- Diketone
LC-MS(APCI)m/z?417(MH+).
1H?NMR(DMSO-d 6)：δ0.76(3H，t)；1.63(2H，q)；1.66-1.76(2H，m)；1.96-2.06(2H，m)；3.12(2H，bt)；3.48，3.35(1H?each，ABq，J＝14.9)；3.32-3.41(2H，m)；5.04-5.12(1H，m)；6.86(1H，d)；7.80(1H，dd)；7.96(1H，s)；8.19(1H，d)；10.73(1H，s)。
LC-MS(APCI)m/z?417(MH+).
5-[({4-[(5-chloropyridine-2-yl) oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-5-propyl imidazole alkane-2,4- Diketone
LC-MS(APCI)m/z?431(MH+).
1H?NMR(DMSO-d 6)：δ0.84(3H，t)；1.03-1.16(1H，m)；1.20-1.35(1H，m)；1.58(2H，t)；1.65-1.77(2H，m)；1.96-2.06(2H，m)；3.11(2H，t)；3.21-3.42(3H，D 2O)；3.48(1H，half?ABq，J＝14.9)；5.04-5.12(1H，m)；6.86(1H，d)；7.80(1H，dd)；7.99(1H，s)；8.19(1H，d)；10.74(1H，s).
5-[({4-[(5-chloropyridine-2-yl) oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-5-(2-methyl-propyl) miaow Azoles alkane-2, the 4-diketone
LC-MS(APCI)m/z?445(MH+).
1H?NMR(DMSO-d 6)：δ0.81(3H，d)；0.88(3H，d)；1.50-1.59(3H，m)；1.64-1.78(2H，m)；1.95-2.05(2H，m)；3.06-3.16(2H，m)；3.22-3.41(3H，D 2O)；3.46(1H?half?Abq，J＝15.1)；5.03-5.12(1H，m)；6.86(1H，d)；7.80(1H，dd)；7.99(1H，bs)；8.19(1H，d)；10.71(1H，bs).
5-[({4-[(5-chloropyridine-2-yl) oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-5-(2-pyrimidine-2-base ethyl) Imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?495(MH+)。
1H?NMR(DMSO-d 6)：δ1.66-1.78(2H，m)；1.96-2.16(4H，m)；2.64-2.76(1H，m)；2.84-2.95(1H，m)；3.08-3.18(2H，m)；3.33-3.41(2H，m)；3.43，3.57(1H?each，ABq，J＝14.9)；5.04-5.12(1H，m)；6.86(1H，d)；7.34(1H，t)；7.80(1H，dd)；8.12(1H，d)；8.19(1H，d)；8.70(1H，d)；10.84(1H，s).
5-[({4-[(5-chloropyridine-2-yl) oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-the 5-[(3-aminomethyl phenyl) first Base] imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?493(MH+).
1H?NMR(DMSO-d 6)：δ1.66-1.78(2H，m)；1.96-2.07(2H，m)；2.23(3H，s)；2.84(2H，s)；3.09-3.20(2H，m)；3.34-3.43(2H，m)；3.45，3.69(1H?each，ABq，J＝14.7Hz)；5.06-5.13(1H，m)；6.87(1H，d)；6.93-6.98(2H，m)；7.01-7.06(1H，m)；7.10-7.17(1H，m)；7.81(1H，dd)；8.08(1H，s)；8.20(1H，d)；10.35(1H，s).
5-[({4-[(5-chloropyridine-2-yl) oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-5-(tetrahydrochysene-2H-pyrans -4-ylmethyl) imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?487(MH+)。
1H?NMR(DMSO-d 6)：δ1.06-1.26(2H，m)；1.39-1.77(7H，m)；1.95-2.05(2H，m)；3.06-3.27(4H，m)；3.27-3.41(3H，D 2O)；3.48(1H?halfABq，J＝15.0Hz)；3.69-3.79(2H，m)；5.03-5.12(1H，m)；6.85(1H，d)；7.80(1H，dd)；8.03(1H，bs)；8.19(1H，d)；10.79(1H，s).
5-[({4-[(5-chloropyridine-2-yl) oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-5-(3-morpholine-4-base propyl group) Imidazolidine-2,4-diketone trifluoroacetic acid
LC-MS(APCI)m/z?517(MH+)。
1H?NMR(DMSO-d 6)：δ1.40-1.78(6H，m)；1.96-2.06(2H，m)；2.94-3.18(6H，m)；3.31-3.44(5H，m)；3.54(1H?half?Abq，J＝14.9Hz)；3.60(2H，t)；3.90-4.01(2H，m)；4.25-6.27(1H)；6.85(1H，d)；7.80(1H，dd)；8.05(1H，bs)；8.19(1H，d)；9.52(1H，bs)；10.88(1H，s).
3-{4-[({4-[(5-chloropyridine-2-yl) oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-2,5-dioxo imidazoles Alkane-4-yl } propionitrile
LC-MS(APCI)m/z?442(MH+).
1H?NMR(DMSO-d 6)：δ1.66-1.78(2H，m)；1.95-2.05(4H，m)；2.37-2.57(2H，DMSO-d 6)；3.07-3.17(2H，m)；3.25-3.40(2H，D 2O)；3.42，3.52(1H?each，Abq，J＝14.7)；5.04-5.12(1H，m)；6.86(1H，d)；7.80(1H，dd)；7.99(1H，bs)；8.20(1H，d)；10.91(1H，s).
3-{4-[({4-[(5-chloropyridine-2-yl) oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-2,5-dioxo imidazoles Alkane-4-yl } propyl carbamic acid 1,1-dimethyl ethyl ester
LC-MS(APCI)m/z?547，490(MH+)；(MH+)-tBu。
1H?NMR(DMSO-d 6)：δ1.10-1.27(1H，m)；1.27-1.43(9H，s)；1.52-1.77(4H，m)；1.94-2.06(2H，m)；2.80-2.90(2H，m)；3.06-3.16(2H，m)；3.22-3.40(4H，D 2O)；3.47(1H?half?ABq，J＝15.1Hz)；5.03-5.12(1H，m)；6.76-6.88(2H，m)；7.80(1H，dd)；7.95(1H，bs)；8.19(1H，d)；10.73(1H，bs).
5-[({4-[(5-chloropyridine-2-yl) oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-5-(2-morpholine-4-base ethyl) Imidazolidine-2, the 4-diketone
Purifying not.
LC-MS(APCI)m/z?502(MH+).
5-[({4-[(5-chloropyridine-2-yl) oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-5-phenylimidazolidines,-2,4- Diketone
Purifying not.
LC-MS(APCI)m/z?465(MH+).
5-[({4-[(5-chloropyridine-2-yl) oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-5-(4-fluorophenyl) imidazoles Alkane-2, the 4-diketone
Purifying not.
LC-MS(APCI)m/z?483(MH+).
5-[({4-[(5-chloropyridine-2-yl) oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-5-(1H-imidazol-4 yl) Imidazolidine-2, the 4-diketone
Purifying not.
LC-MS(APCI)m/z?455(MH+).
4-{4-[({4-[(5-chloropyridine-2-yl) oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-2,5-dioxo imidazoles Alkane-4-yl } benzamide
Purifying not.
LC-MS(APCI)m/z?508(MH+).
5-[({4-[(5-chloropyridine-2-yl) oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-5-[2-(1H-1,2,4-three Azoles-1-yl) ethyl] imidazolidine-2, the 4-diketone
Purifying not.
LC-MS(APCI)m/z?484(MH+).
5-({ [4-(4-fluorophenyl) piperidines-1-yl] alkylsulfonyl } methyl)-5-(2-pyrimidine-2-base ethyl) imidazolidine-2, The 4-diketone
LC-MS(APCI)m/z?462(MH+)。
1H?NMR(DMSO-d 6)：δ1.62(2H，dq)；1.77-1.86(2H，m)；2.07-2.19(2H，m)；2.57-2.76(2H，m)；2.81-2.96(3H，m)；3.42，3.56(1H?each，ABq，J＝14.6Hz)；3.59-3.68(2H，m)；7.11(2H，t)；7.27-7.36(3H，m)；8.08(1H，bs)；8.71(1H，d)；10.84(1H，bs).
5-({ [4-(4-fluorophenyl) piperidines-1-yl] alkylsulfonyl } methyl)-5-(tetrahydrochysene-2H-pyrans-4-ylmethyl) miaow Azoles alkane-2, the 4-diketone
LC-MS(APCI)m/z?454(MH+)。
1H?NMR(DMSO-d 6)：δ1.07-1.28(2H，m)；1.40-1.68(7H，m)；1.77-1.85(2H，m)；2.56-2.67(1H，m)；2.85(2H，dq)；3.22(2H，dq)；3.39-3.45(1H，m)；3.48(1H?half?ABq，J＝14.5Hz)；3.53-3.66(2H，m)；3.75(2H，dt)；7.11(2H，t)；7.26-7.33(2H，m)；8.00(1H，bs)；10.68(1H，bs).
4-[4-({ [4-(4-fluorophenyl) piperidines-1-yl] alkylsulfonyl } methyl)-2,5-dioxo alkyl imidazole-4-yl] benzene Methane amide
LC-MS(APCI)m/z?475(MH+)。
1H?NMR(DMSO-d 6)：δ1.61(2H，dq)；1.77-1.88(2H，m)；2.58-2.69(1H，m)；2.85-3.01(2H，m)；3.60(1H?half?ABq，J＝14.6Hz)；3.60-3.69(2H，m)；7.12(2H，t)；7.26-7.34(2H，m)；7.42(1H，bs)；7.65(2H，d)；7.91(2H，d)；8.01(1H，bs)；8.85(1H，s)；10.95(1H，bs).
5-({ [4-(4-fluorophenyl) piperidines-1-yl] alkylsulfonyl } methyl)-5-(1H-imidazol-4 yl) imidazolidine-2,4- Diketone
Purifying not.
LC-MS(APCI)m/z?422(MH+).
5-([[4-(4-chloro-phenyl-) piperidines-1-yl] alkylsulfonyl } methyl)-5-(tetrahydrochysene-2H-pyrans-4-ylmethyl) miaow Azoles alkane-2, the 4-diketone
LC-MS(APCI)m/z?470(MH+)。
1H?NMR(DMSO-d 6)：δ1.07-1.28(2H，m)；1.40-1.68(7H，m)；1.76-1.85(2H，m)；2.56-2.68(1H，m)；2.85(2H，q)；3.22(2H，q)；3.48(1H?half?ABq，J＝14.5Hz)；3.53-3.67(2H，m)；3.75(2H，t)；7.26-7.37(4H，m)；8.02(1H，bs)；10.79(1H，bs).
5-({ [4-(4-chloro-phenyl-) piperidines-1-yl] alkylsulfonyl } methyl)-5-(3-morpholine-4-base propyl group) imidazolidine-2, 4-diketone trifluoroacetic acid
LC-MS(APCI)m/z?499(MH+)。
1H?NMR(DMSO-d 6)：δ1.41-1.87(8H，m)；2.56-2.69(1H，m)；2.86(2H，q)；2.95-3.14(4H，m)；3.33-3.44(3H，m)；3.52(1H?halfABq，J＝14.6Hz)；3.55-3.69(4H，m)；3.90-4.00(2H，m)；7.25-7.37(4H，m)；8.07(1H，s)；9.89(1H，bs)；10.87(1H，s).
(5R, S)-5-methyl-5-[({4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } alkylsulfonyl) methyl] miaow Azoles alkane-2, the 4-diketone
LC-MS(APCI)m/z?422.1(MH+).
Purity＞95%by NMR.
1H-NMR(DMSO-d 6)：δ10.75(1H，s)；8.44(1H，d)；8.02(1H，s)；7.85(1H，dd)；7.03(1H，d)；3.75(4H，m)；3.55(1H，d)；3.35(1H，d)；3.21(4H，m)；1.31(3H，s).
6-(4-{[({4R, S}-4-methyl-2,5-dioxo alkyl imidazole-4-yl) methyl] alkylsulfonyl } piperazine-1-yl) Pyridine-3-nitrile
LC-MS(APCI)m/z?379.1(MH+).
Purity＞99%by NMR.
1H-NMR(DMSO-d 6)：δ10.74(1H，s)；8.52(1H，d)；8.00(1H，s)；7.90(1H，dd)；7.00(1H，d)；3.78(4H，m)；3.55(1H，d)；3.36(1H，d)；3.20(4H，m)；1.31(3H，s).
(5R, S)-5-({ [4-(4-fluorophenyl) piperazine-1-yl] alkylsulfonyl } methyl)-5-Methylimidazole alkane-2,4-two Ketone
LC-MS(APCI)m/z?371.1(MH+).
Purity＞98%by NMR.
1H-NMR (DMSO-d 6): δ 10.75 (1H, s); 8.03 (1H, s); 7.11-6.95 (4H, m); 3.56 (1H, d); 3.36 (1H, d); 3.25 (4H, m); 3.15 (4H, m); 1.33 (3H, s). (5R, S)-the 5-[({4-[(4-fluorophenyl) methyl] piperazine-1-yl } alkylsulfonyl) methyl]-5-Methylimidazole alkane-2, The 4-diketone
LC-MS(APCI)m/z?385.1(MH+).
Purity＞95%by NMR.
1H-NMR(DMSO-d 6)：δ10.72(1H，s)；7.99(1H，s)；7.33(2H，m)；7.15(2H，m)；3.50(2H，s)；3.49(1H，d)；3.30(1H，d)；3.12(4H，m)；2.42(4H，m)；1.32(3H，s).
(5R, S)-5-methyl-5-{[((4-pyrimidine-2-base piperazine-1-yl) alkylsulfonyl] methyl } imidazolidine-2,4-two Ketone.
LC-MS(APCI)m/z?355.1(MH+).
Purity＞99%by NMR.
1H-NMR(DMSO-d 6)：δ10.74(1H，s)；8.40(2H，d)；8.01(1H，s)；6.68(1H，t)；3.83(4H，m)；3.53(1H，d)；3.33(1H，d)；3.18(4H，m)；1.31(3H，s).
5-(3-aminopropyl)-5-[({4-[(5-chloropyridine-2-yl) oxygen base] piperidines-1-yl } alkylsulfonyl) methyl] imidazoles Alkane-2,4-diketone trifluoroacetic acid
With 3-{4-[({4-[(5-chloropyridine-2-yl) the oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-2,5-dioxo alkyl imidazole-4-base propyl carbamic acid 1, (426mg 0.78mmol) is dissolved in 10mLCH to 1-dimethyl ethyl ester 2Cl 2In and add 4mL TFA.Should react and at room temperature stir 1 hour.Remove and desolvate, obtain 408mg (93%) title compound, be white solid.
LC-MS(APCI)m/z?446(MH+)。
1H?NMR(CD 3OD)：δ1.48-1.63(1H，m)；1.69-1.96(5H，m)；2.01-2.12(2H，m)；2.93(2H，t)；3.20-3.29(2H，m)；3.40，3.60(1H?each?ABq，J＝14.6Hz)；3.44-3.54(2H，m)；4.85(4H，D 2O)；5.14-5.22(1H，m)；6.78(1H，d)；7.67(1H，dd)；8.08(1H，d).
5-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-5-piperidin-4-yl-imidazolidine-2,4- Dione hydrochloride
With 4-{4-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-2,5-dioxo-imidazolidine-4-yl }-(100mg, (ethyl acetate is 30ml) and in the methyl alcohol (5ml) 0.16mmol) to be dissolved in 2M hydrochloric acid for piperidines-1-carboxylic acid tert-butyl ester.Solution was stirred 1 hour at 50 ℃.Evaporation obtains 90.5mg (0.16mmol) title compound 5-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-5-piperidin-4-yl-imidazolidine-2,4-dione hydrochloride, quantitative yield.
LC-MS(APCI)m/z?472.3(MH+).
1H?NMR(DMSO-d 6)：δ10.88(1H，s)；9.05(1H，d)；8.48(1H，m)；8.21(1H，d)；7.82(1H，dd)；6.87?1H，d)；5.10?1H，m)；3.47(2H，s)；3.43-3.13(7H，m)；2.78(2H，m)；2.02-1.39(9H，m).
4-{4-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-2,5-dioxo-imidazolidine-4-yl }-piperidines-1-carboxylic acid tert-butyl ester
Be the preparation feedback ester, piperidines-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester, Albert A Carret al for example, Journal of Organic Chemistry (1990), 55 (4), 1399-401.
LC-MS(APCI)m/z?472.3(MH+-Boc).
5-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-5-(tetrahydrochysene-pyrans-4-yl)-2,4- Diketone
LC-MS(APCI)m/z?403.2(MH+).
1H?NMR(DMSO-d 6)：δ10.77(1H，s)；8.20(1H，d)；8.19(1H，s)；7.81(1H，dd)；6.87(1H，d)；5.09(1H，m)；3.88(2H，t)；3.45(2H，s)；3.38(2H，m)；3.21(2H，t)；3.13(2H，m)；2.02(2H，m)；1.84(1H，t)；1.72(2H，m)；1.60(1H，d)；1.32(4H，m).
5-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-5-pyridin-4-yl-imidazolidine-2,4- The diketone trifluoroacetic acid
LC-MS(APCI)m/z?466.2(MH+).
1H?NMR(DMSO-d 6)：δ11.15(1H，s)；8.97(1H，s)；8.76(2H，d)；8.20(1H，d)；7.82(2H，dd)；7.80(1H，d)；6.86(1H，d)；5.10(1H，m)；4.17(1H，m)；3.73(1H，d)；3.41(2H，m)；3.17(2H，m)；2.08(2H，m)；1.72(2H，m).
4-(4-[({4-[(5-chloropyridine-2-yl) and the oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-2,5-dioxo miaow Azoles alkane-4-yl } methyl) piperidines-1-carboxylic acid 1,1-dimethyl ethyl ester
This title compound basically according to synthetic (5R, S)-5-[4-(4-fluoro-phenyl)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2, the description preparation in the 4-diketone.
LC-MS(APCI)m/z?530(MH+-boc)。
1H?NMR(DMSO-d 6)：δ0.88-1.10(2H，m)；1.30-1.77(16H，m)；1.94-2.06(2H，m)；2.53-2.77(2H，m)；3.05-3.17(2H，m)；3.21-3.41(4H，D 2O)；3.48(1Hhalf?ABq，J＝14.7Hz)；3.73-3.88(2H，m)；5.03-5.12(1H，m)；6.86(1H，d)；7.80(1H，dd)；8.04(1H，bs)；8.19(1H，d)；10.55(1H，bs).
5-[({4-[(5-chloropyridine-2-yl) oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-5-(piperidin-4-yl methyl) Imidazolidine-2,4-diketone trifluoro-acetate
This title compound is according to synthetic 5-(3-aminopropyl)-5-[({4-[(5-chloropyridine-2-yl) the oxygen base] piperidines-1-yl } alkylsulfonyl) methyl] imidazolidine-2, the description preparation in the 4-diketone trifluoroacetic acid.
LC-MS(APCI)m/z?486(MH+)。
1H?NMR(DMSO-d 6)：δ1.17-1.40(2H，m)；1.47-1.81(7H，m)；1.94-2.07(2H，m)；2.75-2.93(2H，m)；3.06-3.42(7H，m)；3.50(1H?halfABq，J＝15.6Hz)；5.04-5.12(1H，m)；6.85(1H，d)；7.80(1H，dd)；8.06(1H，s)；8.08-8.22(2H，m)；8.45(1H，bd)；10.85(1H，s).
N-(3-{4-[({4-[(5-chloropyridine-2-yl) oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-2, the 5-dioxo Imidazolidine-4-yl } propyl group) amsacrine
With 5-(3-aminopropyl)-5-[({4-[(5-chloropyridine-2-yl) the oxygen base] piperidines-1-yl } alkylsulfonyl) methyl] imidazolidine-2; 4-diketone trifluoroacetic acid (100mg; 0.18mmol) slurryization in 2mL DCM, (62L is 0.36mmol) and with this slurry stirred for several minute to add DIPEA.(16 μ L at room temperature stir 0.18mmol) and with reactant and to spend the night to add SULPHURYL CHLORIDE.With the HPLC purifying of thick product by preparing.
LC-MS(APCI)m/z?524(MH+)。
1H?NMR(DMSO-d 6)：δ1.19-1.52(2H，m)；1.58-1.77(4H，m)；1.95-2.06(2H，m)；2.85(3H，s)；2.83-2.93(2H，m)；3.12(2H，t)；3.19-3.46(3H，D 2O)；3.50(1H?half?ABq，J＝15.7Hz)；5.04-5.12(1H，m)；6.86(1H，d)；6.97(1H，t)；7.80(1H，dd)；8.01(1H，s)；8.19(1H，d)；10.79(1H，s).
Embodiment 14
(5R, S)-5-[4-(5-chloro-pyridine-2-yl)-piperazine-1-alkylsulfonyl methyl]-5-(3-pyrimidine-2-base-propyl group)- Imidazolidine-2, the 4-diketone
Figure A0281004101251
With 1-([4-(5-chloro-2-pyridyl)-1-piperazinyl] alkylsulfonyl)-5-(2-pyrimidyl)-2 pentanone (0.397g; 0.936mmol); potassium cyanide (0.122g; 1.87mmol); volatile salt (0.500g, 4.68mmol) and 50% ethanol (4mL) in the bottle of sealing, stirred 17 hours down at 75 ℃ (oil temperature).By rotary evaporation ethanol is removed, pH was is adjusted to 6,, solid is washed with less water, collect also dry down at 45 ℃ in a vacuum suspension filtered with 1M HCl.By add solid sodium chloride to saturated and with acetonitrile (2 * 10mL) extract this mixture recovery more products.Use Na 2SO 4Drying is filtered and concentrated organic phase, obtains gleanings for the second time.The gleanings that merges is dissolved in tetrahydrofuran (THF) (5-10mL), is adsorbed on silicon-dioxide (3 g) and goes up and use and be added on the silicon-dioxide pillar.Use EtOAc, then, obtain 0.30g (65% yield) title compound, be white crystalline solid with EtOAc-MeCN (1: 1) wash-out.
LC-MS(APCI)m/z?494(MH+).
1H NMR (DMSO-d 6) δ 10.78 (1H, bs); 8.70 (2H, d, J=5Hz); 8.13 (1H, d, J=3Hz); 8.02 (1H, s); 7.63 (1H, dd, J 1=3Hz, J 2=9Hz); 7.33 (1H, t, J=5Hz); 6.93 (1H, d, J=10Hz); 3.63-3.56 (4H, m); 3.52 (1H, d, J=14Hz); 3.34 (1H, d, J=14Hz; Because of the water signal fogs), and 3.24-3.14 (4H, m); 2.82 (2H, t, J=7Hz) and 1.79-1.50 (4H, m ' is s). 13C NMR (DMSO-d 6) δ 175.6,169.5,157.2,157.0,156.5,145.6,137.3,119.2,119.1,108.8,62.4,52.7,44.5,38.2,36.4 and 21.2.
Initial substance is by being prepared as follows:
1-([4-(5-chloro-2-pyridyl)-1-piperazinyl] alkylsulfonyl)-5-(2-pyrimidyl)-2 pentanone
Figure A0281004101261
(0.64g, 2.32mmol) stirred solution in dry THF (25mL, 40rel vol) is cooled to-10 ℃ under nitrogen atmosphere, and sulphonamide is precipitated out from solution with 1-(5-chloro-2-pyridyl)-1-methyl sulphonyl piperazine.Will (4.64mL, 4.64mmol) the LHMDS 1M in be added dropwise in 4 minutes in the suspension of sulphonamide, then this mixture was stirred 40min at THF.In 4minn, be added dropwise to 4-(2-pyrimidyl)-ethyl butyrate (0.68g, 3.48mmol) (example 8) in dry THF (6.4mL, 10rel vol), and this mixture stirred 30min.With the saturated NH of this mixture 4Cl (0.64mL, 1rel vol) cancellation also is evaporated to semi-solid residue.Be absorbed into resistates among the DCM (20rel vol) and with organic layer water (15mL, 24rel vol), salt solution (15mL, 24rel vol) washing, and use MgSO 4Dry.Except that desolvating, obtain thick product by rotary evaporation, be pale solid (0.84g, 85%).Thick product by using the Biotage FLASH chromatogram purification of ethyl acetate/isohexane (90: 10) as elutriant, is obtained pure ketone, be white amorphous solid.
1-(5-chloro-2-pyridyl)-1-methyl sulphonyl piperazine
In the solution that in toluene (25 volume), contains 1-(5-chloro-2-pyridyl)-piperazine (1eq.), add triethylamine (1.1eq), and this mixture is cooled to 5 ℃ in ice bath.To slowly add in the refrigerative solution with the methane sulfonyl chloride of toluene (0.5vols) dilution, keep temperature to be lower than 10 ℃.After reinforced the finishing, reactant is warmed to room temperature.Add entry also with this mixture filtration and with filter cake slurryization in toluene (2vols).Then with this filter cake with toluene (2vols) washing, and under 40 ℃ dried overnight in a vacuum.
1-(5-chloro-2-pyridyl)-piperazine
Piperazine (4eq) is dropped in the reactor with solid form.At room temperature, pyridine (1.43vols) is added in the reactor, then add toluene (2.14vols).Final slurry is stirred and under 120 ℃, be heated to backflow, obtain perfect solution.In another container, add 2,5-dichloropyridine (DCP) then adds toluene (1.43vols), so that the solid dissolving.Therefore this dissolving and heat absorbing must be warmed to solution～30 ℃, to obtain perfect solution.The solution that will contain DCP then slowly dropped into reactor in 5 hours enough.This moment, the DCP of residual content should be about 20%.This reaction mixture is kept refluxing.Reactant keep refluxed spend the night so that react and finish.
This reaction mixture is cooled to room temperature, adds entry (6vols) then.With two separate, and with water with toluene (5vols) extract again.Merging two organic layers also, water (6vols) washs again.At last, organic layer is washed with salt solution (6vols).
(5S)-5-[4-(5-chloro-pyridine-2-yl)-piperazine-1-alkylsulfonyl methyl]-5-(3-pyrimidine-2-base-propyl group)-miaow Azoles alkane-2, the 4-diketoneWith (5R)-5-[4-(5-chloro-pyridine-2-yl)-piperazine-1-alkylsulfonyl methyl]-5-(3-pyrimidine-2- Base-propyl group)-and imidazolidine-2, the 4-diketone
Corresponding racemize material is dissolved among 8mL isohexane/EtOH (25/75), and by being separated into pure enantiomorph with following Gilson HPLC system:
Pillar: CHIRALCEL OD, 2.0 * 25cm, flow velocity=6.0mL/min, elutriant=isohexane/EtOH (25/75), temperature=envrionment temperature, detector UV=230nm.
Collect optically active enantiomorph and CHIRALCEL OD-H (0.46 * 25cm, 0.5mL/min, isohexane/EtOH (25/75), envrionment temperature 220nm) goes up and analyzes.
Rt=11.5min.ee＞99%, for the enantiomorph of very fast wash-out, 8.7mg (37%).
LC-MS(APCI)m/z?494.1(MH+).
[α] D＝-26.4°(c＝0.0022g/mL，EtOH，t＝20℃)
Rt=14.5min.ee=98% is for the enantiomorph of slow wash-out, 9mg (39%).
LC-MS(APCI)m/z?494.1(MH+).
[α] D＝+24.5°(c＝0.0026g/mL，EtOH，t＝20℃)
Embodiment 15
Following compound prepares with the method for describing in vitriol embodiment 13 and 14.
Embodiment 16
Compound with following general formula
Figure A0281004101291
According to the method preparation of describing among the embodiment 13.
The ketone intermediate
(1): for the NMR-data, referring to experimental section.
1-(1,1 '-xenyl-4-base sulphur) third-2-ketone
With the 1-[(4-bromophenyl) sulphur] third-2-ketone (357mg, 1.46mmol) usefulness phenyl-boron dihydroxide (231mg, 1.89mmol), [1,1 '-bis (diphenylphosphine) ferrocene] palladium chloride (II) and methylene dichloride title complex (1: 1) (36mg), toluene (20ml), methyl alcohol (7.5ml), saturated sodium carbonate solution (3.5ml) is handled and was stirred together 18 hours.After the cooling, this reaction mixture is handled and is extracted in the ethyl acetate with dilute hydrochloric acid.This product (is used 25% ethyl acetate: the isohexane wash-out), obtain 277 mg products by the flash chromatography purifying on the silica gel.
GC/MS?m/z：242[M +].
1H?NMR(CDCl 3)：δ2.33(3H，s)；3.73(2H，s)；7.37(1H，s)；7.42-7.48(4H，m)；7.54-7.59(4H，m).
Below compound by the description preparation in synthetic 1-(1,1 '-xenyl-4-base sulphur) third-2-ketone.
4 '-[(2-oxopropyl) sulphur]-1,1 '-xenyl-4-nitrile
GC/MS?m/z：267[M+]。
1H?NMR(CDCl 3)：δ2.34(3H，s)；3.75(2H，s)；7.44，7.54(4H，abq，J＝8.5Hz)；7.67，7.74(4H，abq，J＝8.5Hz).
1-(4 '-[(trifluoromethyl) oxygen base]-1,1 '-xenyl-4-yl } sulphur) third-2-ketone
GC/MS?m/z：326[M+].
1H?NMR(CDCl 3)：δ2.34(3H，s)；3.73(2H，s)；7.30(2H，d)；7.43(2H，d)；7.51(2H，d)；7.58(2H，d).
1-(1,1 '-xenyl-4-base alkylsulfonyl) third-2-ketone
(69mg, 0.28mmol) at room temperature (72mg, 0.85mmol), ((525mg, 0.85mmol), water (5ml) and methyl alcohol (10ml) stirred 3 hours oxone third-2-ketone together with sodium bicarbonate with 1-(1,1 '-xenyl-4-base sulphur).Add entry (50ml) and product is extracted into ethyl acetate (in 3 * 25ml).With extract salt water washing, with dried over sodium sulfate and evaporation, obtain 78mg (99%) product, its purity is enough to be not further purified use down.
LC-MS(APCI)m/z?275(MH+)。
1H?NMR(CDCl 3)：δ2.47(3H，s)；4.22(2H，s)；7.44-7.54(3H，m)；7.64(2H，d)；7.80，7.97(4H，abq，J＝8.6Hz).
4 '-[(2-oxopropyl) alkylsulfonyl]-1,1 '-xenyl-4-nitrile
This title compound is according to the description preparation in synthetic 1-(1,1 '-xenyl-4-base alkylsulfonyl) third-2-ketone.
1H?NMR(DMSO-d 6)：δ2.48(3H，s)；4.23(2H，s)；7.74(2H，d)；7.81(4H，t)；8.02(2H，d).
The general formula I I of glycolylurea
Below compound according to synthetic (5R, S)-5-[4-(4-fluoro-phenyl)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2, the description preparation in the 4-diketone (embodiment 13).
Figure A0281004101311
(1): for the NMR data referring to experimental section.
(5R, S)-[4-(5-chloro-pyridine-2-base oxygen base)-benzenesulfonyl methyl]-5-methyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?396(MH+).
1H?NMR(DMSO-d6)：δ1.27(3H，s)；3.71，3.78(1H?each，ABq，J＝15.0)；7.23(1H，d)；7.36-7.41(2H，m)；7.82-7.87(3H，m)；8.04(1H，dd)；8.27(1H，d)；10.79(1H，s).
5-chloro-2-{[4-(methyl sulphonyl) phenyl] the oxygen base } pyridine
With 2,5-dichloropyridine (1.48g; 10mmol), 4-methyl sulphonyl phenol (1.89g; 11mmol) and Cs 2CO 3(4.24g; 13mmol) slurryization in 75mL NMP.This slurry is heated to about 170 ℃ to spend the night.After the cooling, leach Cs 2CO 3And with solvent at H 2Extract between O and the EtOAc.With organic phase at Na 2SO 4Last dry and evaporation.Add heptane: EtOAc 2: 1 in the resistates and leach crystal 1.42g (50%).
LC-MS(APCI)m/z?284(MH+)。
1H?NMR?CDCl 3：δ3.09(3H，s)；7.02(1H，d)；7.33(2H，d)；7.76(1H，dd)；8.00(2H，d)；8.17(1H，s).
5-methyl-5-[({4 '-[(trifluoromethyl) oxygen base]-1,1 '-xenyl-4-yl } sulfinyl) methyl] imidazoles Alkane-2, the 4-diketone
With 5-methyl-5-[({4 '-[(trifluoromethyl) oxygen base]-1,1 '-xenyl-4-yl sulphur) methyl] imidazolidine-2, the 4-diketone (48mg, 0.112mmol) at room temperature with oxone (50mg), sodium bicarbonate (50mg), water (5ml) and methyl alcohol (10ml) stirred 18 hours together.Leach solid and use alcohol crystal, obtain the 20mg title compound.
The extremely weak peak 413 (MH+) of LC-MS (APCI) m/z.
1H?NMR(DMSO-d 6)：δ1.41(3H，s)；3.04-3.27(2H，m)；7.47(2H，d)；7.67-7.73(2H，m)；7.78-7.90(5H，m)；8.21?and?8.37(1H，2s)；10.79?and?10.91(1H，2s).
5-methyl-5-[({4 '-[(trifluoromethyl) oxygen base]-1,1 '-xenyl-4-yl } sulphur) methyl] imidazolidine-2, the 4-diketone
The extremely weak peak 397 (MH+) of LC-MS (APCI) m/z.
1H?NMR(DMSO-d 6)：δ1.33(3H，s)；3.29(2H，s)；7.42-7.45(4H，m)；7.61(2H，d)；7.77(2H，d)；7.99(1H，s)；10.75(1H，s).
5-[(1,1 '-xenyl-4-base alkylsulfonyl) methyl]-5-Methylimidazole alkane-2, the 4-diketone
LC-MS(APCI)m/z?345(MH+)。
1H?NMR(DMSO-d 6)：δ1.27(3H，s)；3.72，3.81(2H，abq，J＝15.3Hz)；7.45(1H，t)；7.52(2H，t)；7.76(2H，d)；7.82(1H，s)；7.88，7.94(4H，abq，J＝8.9Hz)；10.80(1H，bs).
4 '-{ [(4-methyl-2,5-dioxo alkyl imidazole-4-yl) methyl] alkylsulfonyl }-1,1 '-xenyl-4-nitrile
The extremely weak peak 370 (MH+) of LC-MS (APCI) m/z.
1H?NMR(DMSO-d 6)：δ1.26(3H，s)；3.74，3.84(2H，abq，J＝16.0Hz)；7.81(1H，s)；7.91-8.03(8H，m)；10.81(1H，s).
Embodiment 17
Synthetic enantiomer-pure glycolylurea
Figure A0281004101331
Synthetic route provides below.
Figure A0281004101332
Reagent and condition: a) KCN, NH 4CO 3, EtOH/H 2O ,+90 ℃, 3h.b) chiral separation, CHIRALPAK AD, methyl alcohol is as elutriant c) Cl 2(g), AcOH/H 2O,＜+15 ℃, 25min.d) diisopropyl ethyl amine, THF.-20 ℃, 30min.
Experimental procedure
(5S)-and 5-({ [4-(4-fluorophenyl) piperidines-1-yl] alkylsulfonyl } methyl)-5-Methylimidazole alkane-2, the 4-diketone
(63mg 0.29mmol) absorbs in the 3mL dry THF, with diisopropyl ethyl amine (50L, 0.29mmol) neutralization and cooling off in ice-water-bath with 4-(4-fluorophenyl) piperidine hydrochlorate.Add [(4S)-and 4-metyl-2,5-dioxo-imidazoles odin-4-yl] methane sulfonyl chloride (80mg, 0.35mmol), and after stirring 10min, add diisopropyl ethyl amine (50L, 0.29mmol), till this mixture at room temperature stirred ester and show that to LC-MS (APCI) amine consumes.With this reaction mixture evaporation, resistates is absorbed among the EtOH, be heated to 50 ℃, and make its cooling add entry then.The collecting precipitation thing with EtOH/ water washing and dry in a vacuum, obtains 87mg.
LC-MS(APCI)m/z?370(MH+).
1H?NMR(DMSO-d 6)：δ10.73(1H，s)；8.01(1H，s)；7.29(2H，dd)；7.11(2H，dd)；3.61(2H，dd)；3.50，3.33(1H?each，ABq，J＝14.7Hz)；2.91-2.80(2H，m)；2.67-2.57(1H，m)；1.82(2H，d)；1.62(2H，ddd)；1.33(3H，s).
By being prepared as follows initial substance:
5-methyl-5-{[(phenmethyl) sulphur] methyl } imidazolidine-2, the 4-diketone
In stainless steel vessel, drop into second alcohol and water (315mL/135mL).
Add 31.7g (0.175mol) dibenzylsulfide acetone, 22.9g (0.351mol) potassium cyanide and 84.5g (0.879mol) volatile salt.Closed reactor remained on remained under the vigorous stirring in the oil bath (90 ℃ of room temperatures) 3h hour.Reactor is cooled off with ice-water (0.5h), yellow slurry is evaporated to drying, distribute solid residue between 400mL water and the 700mL ethyl acetate and separate.Water is extracted with ethyl acetate (300mL).The organic phase that merges is washed dry (Na with saturated brine (150mL) 2SO 4), filter and be evaporated to drying.If product is non-crystallizable, then the 300mL methylene dichloride is added in the oil.Evaporation obtains product, is buff powder, 43.8g (90%).
LC-MS(APCI)m/z?251.1(MH+).
1H?NMR(DMSO-d 6)δ：10.74(1H，s)；8.00(1H，s)；7.35-7.20(5H，m)；3.76(2H，s)；2.72，2.62(1H?each，ABq，J＝14.0Hz)；1.29(3H，s).
13C?NMR(DMSO-d 6)δ：177.30，156.38，138.11，128.74，128.24，126.77，62.93，37.96，36.39，23.15.
(5S)-and 5-methyl-5-{[(phenmethyl) sulphur] methyl } imidazolidine-2, the 4-diketone
Title compound is by preparing with 250mm * 50mm pillar separation of racemic material on Dynamic Axial CompressionPreparative HPLC system.The stationary phase that uses is CHIRALPAK AD, elutriant=methyl alcohol, flow=89mL/min, temperature=room temperature, UV=220nm, sample concentration=150mg/mL, volume injected=20mL.
Retention time=the 6min. of title compound
The analysis of chiral purity uses the 250mm * 4.6mm CHIRALPAK-AD pillar available from Daicel to carry out flow=0.5mL/min, elutriant=ethanol, UV=220nm, temperature=room temperature.
Retention time=the 9.27min of title compound.
Purity is estimated as＞99%ee.
LC-MS(APCI)m/z?251.1(MH+).
[α] D＝-30.3°(c＝0.01g/mL，MeOH，T＝20℃).
1H?NMR(DMSO-d 6)δ：10.74(1H，s)；8.00(1H，s)；7.35-7.20(5H，m)；3.76(2H，s)；2.72，2.62(1H?each，ABq，J＝14.0Hz)；1.29(3H，s).
13C?NMR(DMSO-d 6)δ：177.30，156.28，138.11，128.74，128.24，126.77，62.93，37.96，36.39，23.15.
(5R)-and 5-methyl-5-{[(phenmethyl) sulphur] methyl } imidazolidine-2, the 4-diketone
Title compound is by preparing with 250mm * 50mm pillar separation of racemic material on Dynamic Axial CompressionPreparative HPLC system.The stationary phase that uses is CHIRALPAK AD, elutriant=methyl alcohol, flow=89mL/min, temperature=room temperature, UV=220nm, sample concentration=150mg/mL, volume injected=20mL.
Retention time=the 10min. of title compound
The analysis of chiral purity uses the 250mm * 4.6mm CHIRALPAK-AD pillar available from Daicel to carry out flow=0.5mL/min, elutriant=ethanol, UV=220nm, temperature=room temperature.
Retention time=the 17.81min. of title compound
Chiral purity＞the 99%ee. that estimates
LC-MS(APCI)m/z?251.0(MH+).
[α] D＝+30.3°(c＝0.01g/mL，MeOH，T＝20℃).
1H?NMR(DMSO-d 6)δ：10.74(1H，s)；8.00(1H，s)；7.35-7.20(5H，m)；3.76(2H，s)；2.72，2.62(1H?each，ABq，J＝14.0Hz)；1.29(3H，s).
13C?NMR(DMSO-d 6)δ：177.31，156.30，138.11，128.74，128.25，126.77，62.94，37.97，36.40，23.16.
[(4S)-and 4-methyl-2,5-dioxo alkyl imidazole-4-yl] methane sulfonyl chloride
With (5S)-5-methyl-5-{[(phenmethyl) sulphur] methyl } imidazolidine-2,4-diketone (42.6g; 0.17mo]) be dissolved in AcOH (450mL) and H 2In the mixture of O (50mL).This mixture is immersed in the ice/water-bath, blast Cl through this solution 2(g), the adjustments of gas flow velocity so that temperature keep below+15 ℃ of .25min after, this solution becomes yellow, LC/MS is carried out in sampling and HPLC analyzes.The proof initial substance consumes.Yellow solution was stirred 30 minutes, form opaque solution/slurry.
On rotatory evaporator, keep+37 ℃ water-bath to evaporate solvent with temperature.Yellow solid is suspended in the toluene (400mL), and on identical rotatory evaporator, removes and desolvate.This is repeated once.
Should thick product be suspended in the isohexane (400mL) and under agitation be warmed to+40 ℃, slurry be cooled to room temperature, then by removing by filter insoluble product, with isohexane (6 * 100mL) washings, and in decompression+50 ℃ of following dried overnight.So obtain product, be buff powder.
Obtain 36.9g (95%) title compound.
Purity (measuring by HPLC)=99%, NMR supports this purity.
[α] D＝-12.4°(c＝0.01g/mL，THF，T＝20℃).
1H?NMR(THF-d 8)：δ9.91(1H，bs)；7.57(1H，s)；4.53，4.44(1H?each，ABq，J＝14.6Hz)；1.52(s，3H，CH 3).
13C?NMR(THF-d 8)：δ174.96；155.86；70.96；61.04；23.66.
[(4R)-and 4-methyl-2,5-dioxo alkyl imidazole-4-yl] the sulfonyl methane fluorine
According to the program that [(4S)-4-methyl-2,5-dioxo alkyl imidazole-4-yl] methane sulfonyl chloride is described
By (5R)-5-methyl-5-{[(phenmethyl) sulphur] methyl } imidazolidine-2, the 4-diketone (10.0g, 40mmol) initial
Obtain 8.78g (96% yield) title compound.
Purity (measuring)＞98%. by NMR
[α] D＝+12.8°(c＝0.01g/mL，THF，T＝20℃).
1H?NMR(THF-d 8)：δ9.91(1H，brs)；7.57(1H，s)；4.53，4.44(1H?each，ABq，J＝14.6Hz)；1.52(s，3H，CH 3).
13C?NMR(THF-d 8)：δ174.96；155.84；70.97；61.04；23.66.
Embodiment 18
Compound with following general formula
Figure A0281004101371
Prepare according to the description among the embodiment 17.
The amine intermediate
Figure A0281004101372
All amine that use all are commercial or previously described.
The 4-{4-[(trifluoromethyl) oxygen base] phenyl } the piperidines trifluoroacetic acid
With Pd (PPh 3) 4(87mg, 0.0075mmol), LiCl (190mg; 4.5mmol), the 4-{[(trifluoromethyl) alkylsulfonyl] the oxygen base }-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (0.50g 1.5mmol); (0.43g is 2.1mmol) with aq Na for 4-(trifluoromethoxy) phenyl-boron dihydroxide 2CO 3The aqueous solution (2mL, 2N solution) mixes in 5.2mL DME and is incorporated in 85 ℃ of heating 3h down, then is cooled to room temperature and under reduced pressure concentrated.At DCM (10mL), Na 2CO 3The aqueous solution (10mL, 2N solution) and dense NH 4Between the OH (0.6mL).(3 * 10mL) extract with DCM with this layer separation and with water layer.With the organic layer drying (Na that merges 2SO 4) and concentrate.By column chromatography (SiO 2, heptane/ethyl acetate/DCM 5: 1: 1) and purifying, obtain 4-[4-(trifluoromethoxy) phenyl]-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (0.27g, 52%).The mixed H down that is incorporated in MeOH (3mL) with this product and 5%Pd/C (30mg) 2(1atm) stir 24h.This mixture is filtered by Celite, and concentrated 4-[4-(trifluoromethoxy) phenyl that obtains] piperidines-1-carboxylic acid tert-butyl ester (0.23g, 86%).Thick product is dissolved among TFA (2mL) and the DCM (4mL), and under RT, stirs 2h.This reaction mixture is concentrated, and the HPLC purifying by preparing, obtain title compound (0.14g, 58%, three step 26%).
LC-MS(APCI)m/z?246(MH+).
1H?NMR(CDCl 3)：δ9.38(1H，bs)；8.97(1H，bs)；7.26(2H，d)；7.20(2H，d)；3.60(2H，bd)；3.07(2H，q)；2.88-2.72(1H，m)；2.18-2.01(4H，m).
19F?NMR(CDCl 3)：δ-58.35(3F)，-76.19(3F).
The 4-[(4-chloro-phenyl-) ethynyl]-1,2,3,6-tetrahydropyridine hydrochloride
With PdCl 2(PPh 3) 2(47mg, 0.07mmol) and CuI (13mg 0.07mmol) is dissolved in Et in nitrogen gas stream 3Among N (2.7mL) and the THF (8.4mL) and stir 10min.Add A 4-{[(trifluoromethyl) alkylsulfonyl] the oxygen base }-3,6-dihydropyridine-1 (2H)-carboxylic acid tertiary butyl ester (0.46g 1.4mmol) and 2-ethynyl pyridine (152L, 1.5mmol) solution in 3.5mL THF.This reaction mixture is stirred 2h under RT, add ether and leach throw out.With the saturated NH of clear solution 4The Cl aqueous solution, water, salt water washing and dry (Na 2SO 4).Concentrate and purifying (SiO by column chromatography 2, heptane/ether 1: 2), obtain the 4-[(4-chloro-phenyl-) ethynyl]-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (0.26g, 58%).This product is dissolved among THF (3mL) and the dense HCl (3mL), and under RT, stirs 30min.Concentrate for several times with toluene and EtOH, obtain title compound (0.20g, 98%, two step 57%).
LC-MS(APCI)m/z?218/220?3∶1(MH+).
1H?NMR(DMSO-d 6)：δ9.25(2H，bs)；7.49-7.44(4H，m)；6.24-6.11(1H，m)；3.75-3.63(2H，m)；3.25-3.15(2H，m)；2.48-2.42(2H，m).
Below amine according to the 4-[(4-chloro-phenyl-) ethynyl]-1,2,3, the similar fashion of describing in the 6-tetrahydropyridine hydrochloride is carried out.
2-(1,2,3,6-tetrahydropyridine-4-ethyl-acetylene base) pyridine
LC-MS(APCI)m/z?185(MH+).
1H?NMR(CDCl 3)：δ8.59-8.55(1H，m)；7.64(1H，dt)；7.43-7.39(1H，m)；7.20(1H，ddd)；6.30(1H，bs)；3.51(2H，q)；3.04(2H，t)；2.37-2.31(2H，m).
4-[(4-methyl base) ethynyl]-1,2,3, the 6-tetrahydropyridine
LC-MS(APCI)m/z?198(MH+).
1H?NMR(CDCl 3)：δ8.91(1H，bs)；7.33(2H，d)；7.15(2H，d)；6.06(1H，bs)；3.93-3.80(2H，m)；3.49-3.335(2H，m)；2.73-2.60(2H，m)；2.37(3H，s).
2-(piperidin-4-yl oxygen base)-5-trifluoromethyl-pyridine
With sodium hydride (0.52g, 12mmol is 55%, in oil) washed twice in hexane, and be suspended in the exsiccant glycol dimethyl ether (30ml).(1.21g 12mmol) is dissolved in the exsiccant glycol dimethyl ether (30ml) with 2-chloro-5-5-flumethiazine with the 4-hydroxy piperidine.This drips of solution is added in sodium hydride-suspension.Reactant is being spent the night 80 ℃ of following stirrings under nitrogen atmosphere under 80 ℃.After the cooling, water carefully added in the mixture and remove and desolvate by rotary evaporation.Resistates is soluble in water and use ethyl acetate extraction.With organic phase at Na 2SO 4Last dry and evaporation.Use silica gel chromatography (with 80: 20: 2 EtOAc/MeOH/Et resistates 3The N wash-out), obtain 1.7g (63%) title compound, be yellow oil, it is at a few hours post crystallization.
LC-MS(APCI)m/z?247.1(MH+)。
1H?NMR(CDCl 3)：δ8.40(1H，s)；7.74(1H，dd，J＝2.52，8.70Hz)；6.78(1H，d，J＝8.74Hz)；5.25-5.17(1H，m)；3.19-3.08(2H，m)；2.83-2.73(2H，m)；2.10-2.00(2H，m)；1.83(1H，s)；1.73-1.62(2H，m).
Below amine by with Synthetic 2-(piperidin-4-yl oxygen base)-5-trifluoromethyl-pyridine in similarly describe and prepare.
6-(piperidin-4-yl oxygen base)-nicotinic acid nitrile (nicotinonitrile)
LC-MS(APCI)m/z?204.2(MH+)。
1H?NMR(CDCl 3)：δ8.45(1H，s)；7.76(1H，dd，J＝2.40，8.77Hz)；6.78(1H，d，J＝8.77Hz)；5.28-5.17(1H，m)；3.19-3.09(2H，m)；2.83-2.74(2H，m)；2.10-2.01
(2H，m)；1.74-1.63(2H，m).
5-methyl-2-(piperidin-4-yl oxygen base)-pyridine
1H NMR (methyl alcohol-d 4): δ 7.90 (1 H, s); 7.46 (1H, dd, J=2.47,8.46Hz); 6.68 (1H, d, J=8.50Hz); 5.07-4.98 (1H, m); 3.15-3.07 (2H, m); 2.82-2.73 (2H, m); 2.23 (3H, s); 2.07-1.97 (2H, m); 1.84-1.74 (2H, m).
2-methoxyl group-6-(piperidin-4-yl oxygen base)-pyridine
1H?NMR(CDCl 3)：δ7.44(1H，t，J＝7.90Hz)；7.25(2H，dd，J＝1.83，7.90Hz)；5.19-5.11(1H，m)；3.82(3H，s)；3.23-3.16(2H，m)；2.96-2.88(2H，m)；2.13-2.05(2H，m)；1.89-1.79(2H，m).
2-chloro-6-(piperidin-4-yl oxygen base)-pyridine
1H NMR (methyl alcohol-d 4): δ 7.64 (1H, dd, J=7.60,8.22Hz); 6.96 (1H, dd, J=0.66,7.60Hz); 6.73 (1H, dd, J=0.60,8.19Hz); 5.25-5.14 (1H, m); 3.28-3.18 (2H, m); 3.05-2.94 (2H, m); 2.19-2.07 (2H, m); 1.93-1.80 (2H, m).
5-fluoro-2-(piperidin-4-yl oxygen base)-pyrimidine
1H?NMR(CDCl 3)：δ8.36(2H，s)；5.16-5.06(1H，m)；3.29-3.18(2H，m)；2.98-2.87(2H，m)；2.21-2.08(2H，m)；1.97-1.81(2H，m).
2-(piperidin-4-yl oxygen base)-4-trifluoromethyl-pyrimidine
1H?NMR(CDCl 3)：δ8.75(1H，d，J＝4.93Hz)；7.27(1H，d，J＝5.07Hz)；5.39-5.30(1H，m)；3.44-3.33(2H，m)；3.28-3.17(2H，m)；2.35-2.10(4H，m).
5-ethyl-2-(piperidin-4-yl oxygen base)-pyrimidine
1H NMR (methyl alcohol-d 4): δ 8.40 (2H, s); 5.16-5.08 (1H, m); 3.16-3.06 (2H, m); 2.77-2.70 (2H, m); 2.60 (2H, q, J=7.66,15.28Hz); 2.10-2.00 (2H, m); 1.76-1.66 (2H, m); 1.23 (3H, t, J=7.63Hz).
5-methoxyl group-2-(piperidin-4-yl oxygen base)-pyridine; Hydrochloric acid
(45mg 0.14mmol) is dissolved among the THF (3ml) and adds dense HCl (2ml) 4-(5-methoxyl group-pyridine-2-base oxygen base)-piperidines-1-carboxylic acid tert-butyl ester.This reactant was at room temperature stirred 2 hours, remove in a vacuum then and desolvate, the water of remnants is removed by the permanent fluorine evaporation of using EtOH/ toluene, obtain 35mg (97%) title compound, be the oily crystal.
LC-MS(APCI)m/z?225.1(MH+).
Initial substance is by being prepared as follows:
2-chloro-5-methoxyl group-pyridine 1-oxide compound
With 2-chloro-5-methoxyl group-pyridine (200mg, 1.39mmol) and mCPBA (360mg 2.09mmol) is dissolved in CH 2Cl 2(10ml).This mixture was at room temperature stirred 2 days.Then with this mixture CH 2Cl 210%K is used in dilution 2CO 3The aqueous solution and salt water washing, and at Na 2SO 4Last dry.Solvent is removed in a vacuum, obtained 140mg (63%) title compound, be white crystal.
1H?NMR(DMSO-d 6)：δ8.30(1H，d，J＝2.72Hz)；7.68(1H，d，J＝9.23Hz)；7.08(1H，dd，J＝2.70，9.23Hz)；3.31(3H，s).
4-(5-methoxyl group-1-oxygen base-pyridine-2-base oxygen base)-piperidines-1-carboxylic acid tert-butyl ester
With potassium tert.-butoxide (128mg 1.14mmol) is dissolved among the exsiccant THF (10ml), and under nitrogen atmosphere, add the 4-hydroxy-piperdine-1-carboxylic acid tert-butyl ester be dissolved among the THF (5ml) (177mg, 0.88mmol).This mixture was at room temperature stirred 10 minutes, add then the 2-chloro-5-methoxyl group-pyridine 1-oxide compound be dissolved in the dry THF (5ml) (140mg, 0.88mmol).This reaction mixture was at room temperature stirred 3 days.Except that desolvating and resistates being distributed in H 2O and CHCl 3Between.With organic phase usefulness salt water washing and at Na 2SO 4Last drying is removed solvent in a vacuum, obtains 245mg (86%) title compound, is brown oil.
1H?NMR(CDCl 3)：δ7.95-7.93(1H，m)；6.86-6.84(2H，m)；4.95-4.85(1H，m)；3.79(3H，s)；3.25-3.14(2H，m)；3.07-2.96(2H，m)；1.98-1.79(4H，m)；1.46(9H，s).
4-(5-methoxyl group-pyridine-2-base oxygen base)-piperidines-1-carboxylic acid tert-butyl ester
(5-methoxyl group-1-oxygen base-pyridine-2-base oxygen base)-(200mg 0.62mmol) is dissolved among the EtOH (5ml) piperidines-1-carboxylic acid tert-butyl ester with 4-.(498mg is 4.34mmol) with saturated NH with indium 4Cl (4ml) adds in this solution, and reactant was refluxed 4 days.After the cooling, this mixture is filtered by celite, and remove in a vacuum and desolvate.Resistates with silica gel chromatography (with 5: 1 heptane/EtOAc wash-outs) purifying, is obtained 50mg (26%) title compound, be yellow oil.
1H?NMR(CDCl 3)：δ7.77(1H，d，J＝3.06Hz)；7.20(1H，dd，J＝3.07，8.89Hz)；6.66(1H，d，J＝8.99Hz)；5.14-5.07(1H，m)；3.80(3H，s)；3.79-3.72(2H，m)；3.31-3.23(2H，m)；2.00-1.91(2H，m)；1.75-1.64(2H，m)；1.47(9H，s).
4-(4-pyridin-3-yl-phenyl) piperazine; Hydrochloride
(60mg, 0.18mmol) in THF (3ml) and dense HCl (3ml) stirred 1 hour with 4-(4-pyridin-3-yl-phenyl) piperazine-1-carboxylic acid tert-butyl ester.Remove in a vacuum and desolvate, the water of remnants is removed by the permanent fluorine evaporation of using EtOH/ toluene, obtain 50mg (100%) title compound, yellow powder
LC-MS(APCI)m/z?240.2(MH+).
By being prepared as follows initial substance:
4-(4-iodophenyl) piperazine-1-carboxylic acid tert-butyl esterAccording to La Clair at Angew.Chem.Int.Ed.1998,37 (3), the description among the 325-329 with 55% total recovery by the initial preparation of N-phenylpiperazine (19mmol).
4-(4-pyridin-3-yl-phenyl) piperazine-1-carboxylic acid tert-butyl ester
(Ref.Wellmar? et? al.J.Heterocycl.Chem.32(4)，1995，1159-1164.)
4-(4-Iodo phenyl) piperazine-1-carboxylic acid tert-butyl ester (0.272g, 0.70mmol), 3-pyridyl boric acid (0.078g, 0.64mmol), tetrakis triphenylphosphine palladium (0.024g, 0.02mmol), 1M sodium bicarbonate (1.0mL) and 1,2-di methyl ethyl ether (1.5mL) stirred 3 hours down at 84 ℃ under nitrogen atmosphere, absorbed as also water and salt water washing in the ethyl acetate.Organic phase in anhydrous sodium sulphate, is filtered, concentrate with silica gel (1g) by rotatory evaporator and obtain solid, it is applied on the short silicagel column.Use methylene dichloride, methylene dichloride/ethyl diacetate (4: 1) and the washing of pure ethyl diacetate obtain 0.060g (32% yield) title compound, are respectively white solid and 0.060 g initial substance (iodide).By the iodide amount calculated yield that transforms.
LC-MS(APCI)m/z?340.3(MH+)。
1H NMR (methyl alcohol-d 4): δ 8.75 (1H, d, J=2.0Hz); 8.43 (1H, m); 8.04 (1H, m); 7.58 (2H, d, J=8.0Hz); 7.47 (1H, m); 7.10 (2H, d, J=8.0Hz); 3.59 (4H, m); 3.22 (4H, m); 1.50 (9H, s).
N-[3-(piperidin-4-yl oxygen base)-phenyl]-ethanamide; Hydrochloride
(300mg 1.5mmol) is dissolved in dry CH to 4-hydroxy-piperdine-1-carboxylic acid tert-butyl ester 2Cl 2In and be cooled to-10 ℃.Adding in conjunction with the polymkeric substance of triphenylphosphine (750mg, 2.25mmol) and make its swelling.(340mg 2.25mmol) and with reactant stirred 10 minutes down at-10 ℃, and (0.35ml 2.25mmol) is added dropwise in this mixture with DEAD then to add N-(3-hydroxyl-phenyl)-ethanamide that is dissolved in the dry THF.The reaction mixture stirring is spent the night, make its temperature rise to room temperature.This polymkeric substance is leached with short filler silica gel (with toluene/EtOAc (5: 1) as elutriant).By the volume of rotary evaporation reduction merging and with solution the 5%KOH aqueous solution and water washing, at Na 2SO 4Last dry and solvent removed in a vacuum.The gained white powder is dissolved among THF (10ml) and the dense HCl (10ml) and at room temperature stirs 1hr.Solvent is evaporated in a vacuum, and the water of remnants is removed by the permanent fluorine evaporation of using EtOH/ toluene, obtain 230mg (57%) title compound, be white powder
LC-MS(APCI)m/z?235.1(MH+).
Below amine by with synthesize N-[3-(piperidin-4-yl oxygen base)-phenyl]-similar fashion described in the ethanamide carries out
3-(piperidin-4-yl oxygen base)-benzonitrile
LC-MS(APCI)m/z?203.2(MH+).
4-(3-methoxyl group-phenoxy group)-piperidines
LC-MS(APCI)m/z?208.2(MH+).
4-(3-trifluoromethoxy-phenoxy group)-piperidines
LC-MS(APCI)m/z?262.1(MH+).
4-(2,4--two fluoro-phenoxy groups)-piperidines
LC-MS(APCI)m/z?214.2(MH+).
4-(4-chloro-phenoxy group)-piperidines
LC-MS(APCI)m/z?212.2(MH+).
4-(piperidin-4-yl oxygen base)-benzonitrile
LC-MS(APCI)m/z?203.2(MH+).
4-(4-methoxyl group-phenoxy group)-piperidines
LC-MS(APCI)m/z?208.2(MH+).
4-(3,4-two chloro-phenoxy groups)-piperidines
LC-MS(APCI)m/z?246.1(MH+).
4-(3,4--two fluoro-phenoxy groups)-piperidines
LC-MS(APCI)m/z?214.2(MH+).
N-[4-(piperidin-4-yl oxygen base)-phenyl]-ethanamide
LC-MS(APCI)m/z?235.1(MH+).
4-{[(3, the 4-3,5-dimethylphenyl) methyl] the oxygen base } piperidine hydrochlorate
LC-MS(APCI)m/z?220(MH+).
4-{[(2, the 5-3,5-dimethylphenyl) methyl] the oxygen base } piperidine hydrochlorate
LC-MS(APCI)m/z?220(MH+).
5-chloro-2-piperidin-4-yl pyridine hydrochloride
(225mg 3.5mmol) stirs in THF (1mL) under Ar, and at room temperature adds glycol dibromide (50L) with zinc powder.With this mixture heating up to 65 ℃, heated 3 minutes, and make it be cooled to room temperature, add trimethylsilyl chloride (70L) then and this mixture is at room temperature stirred 30min.Slowly add 4-iodo-N-Boc-piperidines (840mg, the 2.7mmol) solution in THF (1.5mL), and this reaction mixture stirred down 2h at 40 ℃.With Pd 2(dba) 3(22mg, 0.024mmol) and P (2-furyl) 3(23mg 0.10mmol) mixes in THF (0.5mL), and this mixture is at room temperature stirred 10min, adds then in the organic zinc reaction soln, then be added in 2-bromo-5-chloro-pyridine among the THF (1mL) (624mg, 3.24mmol) and DMA (4mL).This reaction mixture at 80 ℃ of heating 3h, then is cooled to room temperature, dilutes by the Celite filtration and with EtOAc then.Filtrate is used NaHCO 3The aqueous solution and salt water washing.Dry Na 2SO 4And concentrate.At SiO 2Go up (with 2: 1 wash-outs of 95: 5 to of heptane/EtOAc) purifying, obtain 4-(5-chloropyridine-2-yl) piperidines-1-carboxylic acid tertiary butyl ester, be yellow oil (128mg, 16%).This oil is dissolved in THF (1.5mL) and dense HCl (1.5mL), and under RT, stirs 30min.Concentrate for several times with toluene and EtOH, obtain title compound (89mg, 89%)
LC-MS(APCI)m/z?197(MH+).
1H?NMR(MeOD-d 4)：δ8.54(1H，d)；7.86(1H，dd)；7.38(1H，d)；3.55-3-45(2H，m)；3.22-3.06(3H，m)；2.19-2.09(2H，m)；2.08-1.98(2H，m).
5-benzyloxy-2-(piperidin-4-yl oxygen base)-pyridine; Hydrochloride
This amine by with synthesize the same way as preparation of describing in 5-methoxyl group-2-(piperidin-4-yl oxygen base)-pyridine.
LC-MS(APCI)m/z?285(MH+).
By being prepared as follows initial substance:
2-chloro-5-benzyloxy pyridine
The sodium hydride that will in hexane, wash (55%, in oil, 236mg, 5.40mmol) (350mg 2.70mmol) is suspended in exsiccant DMF (among the 20ml with 2-chloro-5-pyridone.After at room temperature 10 minutes, add bromotoluene (0.32ml, 2.70mmol), and with this mixture restir 2 hours.Extract with the reaction mass dilute with water and with EtOAc (3*50ml).With organic layer water and the salt water washing that merges, at Na 2SO 4Last dry.Except that desolvating, obtain 520mg (88%) title compound by rotary evaporation, be yellow oil.
LC-MS(APCI)m/z?220(MH+).
1H?NMR(CDCl 3)：δ8.19(1H，d，J＝3.00Hz)；7.55(1H，dd，J＝3.15，8.81Hz)；7.48-7.31(6H，m)；5.19(2H，s).
2-chloro-5-benzyloxy-pyridine 1-oxide compound
Will by with Synthetic 2-chloro-5-methoxyl group-pyridine 1-oxide compound in describe identical mode and prepare.
LC-MS(APCI)m/z?236(MH+).
1H?NMR(DMSO-d 6)：δ8.38(1H，d，J＝2.61Hz)；7.69(1H，d，J＝9.28Hz)；7.47-7.33(5H，m)；7.15(1H，dd，J＝2.69，9.15Hz)；5.19(2H，s).
4-(5-benzyloxy-1-oxygen base-pyridine-2-base oxygen base)-piperidines-1-carboxylic acid tert-butyl ester
This compound is by the description preparation in synthetic 4-(5-methoxyl group-1-oxygen base-pyridine-2-base oxygen base)-piperidines-1-carboxylic acid tert-butyl ester.
LC-MS(APCI)m/z?401(MH+).
1H?NMR(DMSO-d 6)：δ8.12(1H，d，J＝2.79Hz)；7.48-7.32(5H，m)；7.19(1H，d，J＝9.16Hz)；7.07(1H，dd，J＝2.88，9.18Hz)；5.13(2H，s)；4.84-4.76(1H，m)；3.20-3.11(2H，m)；3.00-2.87(2H，m)；1.86-1.78(2H，m)；1.59-1.49(2H，m)；1.40(9H，s).
4-(5-benzyloxy-pyridine-2-base oxygen base)-piperidines-1-carboxylic acid tert-butyl ester
This compound is by the description preparation in synthetic 4-(5-methoxyl group-pyridine-2-base oxygen base)-piperidines-1-carboxylic acid tert-butyl ester.
LC-MS(APCI)m/z?385(MH+).
1H?NMR(CDCl 3)：δ7.86(1H，d，J＝3.10Hz)；7.46-7.32(5H，m)；7.28(1H，dd，J＝3.16，9.04Hz)；6.67(1H，d，J＝9.04Hz)；5.16-5.08(1H，m)；5.05(2H，s)；3.84-3.72(2H，m)；3.33-3.25(2H，m)；2.02-1.93(2H，m)；1.76-1.66(2H，m)；1.49(9H，s).
5-hydroxyl-2-(piperidin-4-yl oxygen base)-pyridine trifluoroacetic acid
(5-benzyloxy-1-oxygen base-pyridine-2-base oxygen base)-(476mg 1.19mmol) is dissolved in the methyl alcohol (20ml) piperidines-1-carboxylic acid tert-butyl ester, and adds Pd (OH) with 4- 2(30mg).With the hydrogenation 24 hours under 1atm and room temperature of this mixture.Leach catalyzer T, and, after lyophilize, obtain 110mg (30%) title compound, be aTFA-salt the purifying HPLC of this mixture with preparation, and the neutral protection of 34mg (10%) intermediate.
LC-MS(APCI)m/z?195(MH+).
1H?NMR(DMSO-d 6)：δ7.66(1H，d，J＝2.94Hz)；7.20(1H，dd，J＝3.07，8.82Hz)；6.68(1H，d，J＝8.93Hz)；5.12-5.00(1H，m)；3.29-3.00(4H，m)；2.16-2.02(2H，m)；1.93-1.75(2H，m).
5-bromo-2-(piperidin-4-yl oxygen base)-pyridine hydrochloride
The same way as preparation of describing in this amine amine and synthetic 5-methoxyl group-2-(piperidin-4-yl oxygen base)-pyridine.
LC-MS(APCI)m/z?257+259(MH+)
This initial substance is by the description preparation in synthetic 4-(5-methoxyl group-pyridine-2-base oxygen base)-piperidines-1-carboxylic acid tert-butyl ester.
4-(5-bromo-pyridine-2-base oxygen base)-piperidines-1-carboxylic acid tert-butyl ester
LC-MS(APCI)m/z?357+359(MH+).
1H?NMR(DMSO-d 6)：δ8.26(1H，dd，J＝0.53，2.67Hz)；7.88(1H，dd，J＝2.66，8.81Hz)；6.80(1H，dd，J＝0.53，8.79Hz)；5.15-5.07(1H，m)；3.72-3.64(2H，m)；3.20-3.09(2H，m)；1.97-1.88(2H，m)；1.58-1.48(2H，m)；1.40(9H，s).
4-(5-(4-fluoro-phenyl)-pyridine-2-yl)-piperazine hydrochloride
4-(5-(4-fluoro-phenyl)-pyridine-2-yl)-piperazine-1-aldehyde (carbaldehyde) (98mg, 0.34mmol) be dissolved among the MeOH (5ml) and add dense HCl (12M, 5ml).This mixture at room temperature stirs and spends the night.Solvent evaporated in a vacuum and the water of remnants is removed by the azeotropic evaporation of using EtOH/ toluene, obtain 102mg (100%) title compound, be yellow powder.
LC-MS(APCI)m/z?258(MH+).
Initial substance is by being prepared as follows:
4-(5-(4-fluoro-phenyl)-pyridine-2-yl)-piperazine-1-aldehyde (carbaldehyde)
With 4-(5-bromo-pyridine-2-yl)-piperazine-1-aldehyde (carbaldehyde) (100mg, 0.37mmol), 4-fluorobenzoic boric acid (55mg, 0.39mmol), (1,1 '-two (diphenylphosphine) ferrocene)-dichloro palladium (II) (10mg, 0.01mmol), toluene (2ml), EtOH (0.5ml) and 2M Na 2CO 3Solution (0.5ml, 1mmol) under 80 ℃ under nitrogen heated overnight.After the cooling, this mixture is also separated with dilution with toluene.With organic phase water and salt water washing, by the filtration of celite pad and at Na 2SO 4Last dry.Solvent is removed in a vacuum, obtained 100mg (94%) title compound, be brown ceramic powder.
LC-MS(APCI)m/z?286(MH+).
1H?NMR(DMSO-d 6)：δ8.44(1H，d，J＝2.66Hz)；8.10(1H，s)；7.97(1H，dd，J＝2.52，8.82Hz)；7.70-7.31(2H，m)；7.31-7.21(2H，m)；6.97(1H，d，J＝8.97Hz)；3.65-3.43(8H，m).
This compound prepares by the description in synthetic 4-(5-(4-fluoro-phenyl)-pyridine-2-yl)-piperazine hydrochloride:
4-(5-(4-methoxyl group-phenyl)-pyridine-2-yl)-piperazine hydrochloride
LC-MS(APCI)m/z?270(MH+).
4-(5-(4-chloro-phenyl)-pyridine-2-yl)-piperazine hydrochloride
LC-MS(APCI)m/z?274，276(MH+).
4-(5-(4-trifluoromethoxy-phenyl)-pyridine-2-yl)-piperazine hydrochloride
LC-MS(APCI)m/z?324(MH+).
4-(5-furans-2-base-pyridine-2-yl)-piperazine hydrochloride
LC-MS(APCI)m/z?230(MH+).
4-(5-(1H-pyrroles-2-yl)-pyridine-2-yl)-piperazine dihydrochloride
Title compound is by 2-(6-(4-formyl radical-piperazine-1-yl)-pyridin-3-yl)-pyrroles-1-carboxylic acid tert-butyl ester preparation
LC-MS(APCI)m/z?229(MH+).
4-[3,3 ']-bipyridyl-6-base-piperazine hydrochloride
LC-MS(APCI)m/z?241(MH+).
4-(6-piperazine-1-base-pyridin-3-yl)-benzonitrile hydrochloride
LC-MS(APCI)m/z?265(MH+).
The glycolylurea of general formula I I
Figure A0281004101521
Figure A0281004101541
Figure A0281004101551
(1): for the NMR data referring to experimental section.
Following compound is by synthetic (5S)-5-({ [4-(4-fluorophenyl) piperidines-1-yl] alkylsulfonyl } methyl)-5-Methylimidazole alkane-2; the identical mode of 4-diketone (embodiment 17) prepares, and by the precipitation and with the EtOH/ water washing or by the preparation the HPLC purifying.
(5S)-5-methyl-5-([4-[4-(methyl oxygen base) phenyl]-3,6-dihydropyridine-1 (2H)-yl] alkylsulfonyl } Methyl) imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?380(MH+).
1H NMR (methyl alcohol-d 4): δ 7.35 (2 H, d, J=8.9Hz); 6.87 (2 H, d, J=8.9Hz); 6.01 (1H, dd); 3.92 (2H, dd); 3.78 (3H, s); 3.56,3.41 (1H each, ABq, J=14.6Hz); 3.51-3.46 (2H, m); 2.62-2.57 (2H, m); 1.47 (3H, s).
(5S)-and 5-methyl-5-[({4-[4-(methyl oxygen base) phenyl] piperidines-1-yl } alkylsulfonyl) methyl] imidazolidine-2, The 4-diketone
LC-MS(APCI)m/z?382(MH+).
1H?NMR(DMSO-d 6)：δ10.73(1H，s)；8.01(1H，s)；7.17(2H，d)；6.85(2H，d)；3.71(3H，s)；3.60(2H，dd)；3.50(1H，part?of?ABq，J＝14.8Hz)；2.85(2H，q)；2.54(1H，t)；1.79(2H，d)；1.64-1.53(2H，m)；1.33(3H，s).
(5S)-5-({ [4-(4-chloro-phenyl-)-4-hydroxy piperidine-1-yl] alkylsulfonyl } methyl)-5-Methylimidazole alkane-2, The 4-diketone
LC-MS(APCI)m/z?402/404?3∶1(MH+).
1H?NMR(DMSO-d 6)：δ10.72(1H，s)；8.01(1H，s)；7.51(2H，d)；7.37(2H，d)；5.22(1H，s)；3.49，3.34(1?H?each，ABq，J＝14.9Hz)；3.47-3.35(2H，m)；3.15(2H，q)；1.93(2H，t)；1.64(2H，d)；1.33(3H，s).
(5S)-and 5-methyl-5-[({4-[2-(methyl oxygen base) phenyl] piperidines-1-yl } alkylsulfonyl) methyl] imidazolidine-2, The 4-diketone
LC-MS(APCI)m/z?382(MH+).
1H?NMR(DMSO-d 6)：δ10.72(1H，s)；8.01(1H，s)；7.24-7.14(2H，m)；6.96(1H，d)；6.90(1H，t)；3.78(3H，s)；3.60(2H，dd)；3.51，3.33(1H?each，ABq，J＝14.7Hz)；3.02-2.94(1H，m)；2.88(2H，q)；1.77(2H，d)；1.66-1.56(2H，m)；1.33(3H，s).
(5S)-and 5-methyl-5-[({4-[4-(trifluoromethyl) phenyl] piperidines-1-yl } alkylsulfonyl) methyl] imidazolidine-2, The 4-diketone
LC-MS(APCI)m/z?420(MH+).
1H?NMR(DMSO-d 6)：δ10.73(1H，s)；8.01(1H，s)；7.66(2H，d)；7.50(2H，d)；3.63(2H，dd)；3.52，3.34(1H?each，ABq，J＝14.9Hz)；2.88(2H，ddd)；2.79-2.68(1H，m)；1.86(2H，d)；1.67(2H，ddd)；1.33(3H，s).
(5S)-and 5-methyl-5-[({4-[3-(trifluoromethyl) phenyl] piperidines-1-yl } alkylsulfonyl) methyl] imidazolidine-2, The 4-diketone
LC-MS(APCI)m/z?420(MH+).
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；8.02(1H，s)；7.63-7.52(4H，m)；3.63(2H，dd)；3.52(1H，part?of?ABq，J＝14.9Hz)；2.87(2H，ddd)；2.79-2.70(1H，m)；1.87(2H，d)；1.75-1.63(2H，m)；1.33(3H，s).
(5S)-and 5-[({4-[3, two (trifluoromethyl) phenyl of 5-] piperidines-1-yl } alkylsulfonyl) methyl]-the 5-Methylimidazole Alkane-2, the 4-diketone
LC-MS(APCI)m/z?488(MH+).
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；8.02(1H，s)；8.00(2H，s)；7.93(1H，s)；3.64(2H，dd)；3.52(1H，part?of?ABq，J＝14.9Hz)；2.95-2.81(3H，m)；1.89(2H，d)；1.83-1.69(2H，m)；1.34(3H，s).
(5S)-5-({ [4-(4-chloro-phenyl-)-3,6-dihydropyridine-1 (2H)-yl] alkylsulfonyl } methyl)-5-Methylimidazole Alkane-2, the 4-diketone
LC-MS(APCI)m/z?384/386?3∶1(MH+).
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；8.03(1H，s)；7.47(2H，d)；7.40(2H，d)；6.23(1H，app?s)；3.85(2H，app?s)；3.52，3.39(1H?each，ABq，J＝14.7Hz)；3.39-3.32(2H，m)；2.55(2H，br?s)；1.32(3H，s).
(5S)-and 5-({ [4-(3-fluorophenyl) piperidines-1-yl] alkylsulfonyl } methyl)-5-Methylimidazole alkane-2, the 4-diketone
LC-MS(APCI)m/z?370(MH+).
1H?NMR(DMSO-d 6)：δ10.73(1H，s)；8.01(1H，s)；7.38-7.31(1H，m)；7.15-7.08(2H，m)；7.05-6.98(1H，m)；3.62(2H，dd)；3.51，3.33(1H?each，ABq，J＝14.7Hz)；2.95-2.80(2H，m)；2.68-2.60(1H，m)；1.82(2H，br?d)；1.69-1.58(2H，m)；1.33(3H，s).
(5S)-and 5-({ [4-(2-fluorophenyl) piperidines-1-yl] alkylsulfonyl } methyl)-5-Methylimidazole alkane-2, the 4-diketone
LC-MS(APCI)m/z?370(MH+).
1H?NMR(DMSO-d 6)：δ10.73(1H，s)；8.01(1H，s)；7.36(1H，t)；7.30-7.20(1H，m)；7.18-7.12(2H，m)；3.63(2H，dd)；3.52，3.33(1H?each，ABq)；2.96-2.85(3H，m)；1.80(2H，brd)；1.69(2H，ddd)；1.33(3H，s).
(5S)-and 5-methyl-5-({ [4-(4-aminomethyl phenyl) piperidines-1-yl] alkylsulfonyl } methyl) imidazolidine-2,4-two Ketone
LC-MS(APCI)m/z?366(MH+).
1H?NMR(DMSO-d 6)：δ10.73(1H，s)；8.01(1H，s)；7.15-7.07(4H，m)；3.60(2H，dd)；3.50，3.32(1H?each，ABq)；2.85(2H，q)；2.59-2.51(1H，m)；2.25(3H，s)；1.79(2H，br?d)；1.60(2H，ddd).
(5S)-and 5-methyl-5-({ [4-(phenmethyl) piperidines-1-yl] alkylsulfonyl } methyl) imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?366(MH+).
1H?NMR(DMSO-d 6)：δ10.70(1H，s)；7.96(1H，s)；7.29-7.15(5H，m)；3.46(2H，t)；3.41，3.24(1H?each，ABq，J＝14.9Hz)；2.68(2H，dt)；2.52(2H，d)；1.54-1.51(3H，m)；1.30(3H，s).
(5S)-5-[(1,4 '-bi piperidines-1 '-the Ji alkylsulfonyl) methyl]-5-Methylimidazole alkane-2,4-diketone trifluoro second Acid
LC-MS(APCI)m/z?359(MH+).
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；9.25(1H，br?s)；8.02(1H，s)；3.63(2H，t)；3.51，3.34(1H?each，ABq，J＝14.8Hz)；3.39(2H，d)；3.24(1H，t)；2.92(2H，q)；2.81(2H，t)；2.07(2H，d)；1.82(2H，d)；1.74-1.58(5H，m)；1.45-1.34(1H，m)；1.31(3H，s).
19F?NMR(DMSO-d 6)：δ-74.48.
(5S)-5-({ [4-(3-furans-2-base-1H-pyrazoles-5-yl) piperidines-1-yl] alkylsulfonyl } methyl)-5-methyl Imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?408(MH+).
1H?NMR(DMSO-d 6)：δ10.73(1H，s)；8.01(1H，s)；7.66(1H，s)；6.64(1H，s)；6.53(1H，s)；6.34(1H，s)；3.61-3.49(2H，m)；3.49(1H，half?ABq，J＝14.9Hz)；2.94-2.84(2H，m)；2.81-2.72(1H，m)；1.98(2H，br?d)；1.70-1.58(2H，m)；1.32(3H，s).
(5S)-and 5-methyl-5-{[(4-{4-[(trifluoromethyl) the oxygen base] phenyl } piperidines-1-yl) alkylsulfonyl] methyl } miaow Azoles alkane-2, the 4-diketone
LC-MS(APCI)m/z?436(MH+).
1H?NMR(DMSO-d 6)：δ10.73(1H，s)；8.01(1H，s)；7.40(2H，d)；7.28(2H，d)；3.70-3.55(2H，m)；3.51，3.33(1H?each，ABq，J＝14.7Hz)；2.94-2.80(2H，m)；2.73-2.61(2H，m)；1.86(2H，d)；1.71-1.57(2H，m)；1.33(3H，s).
(5S)-and 5-({ [4-(4-chloro-phenyl-) piperidines-1-yl] alkylsulfonyl } methyl)-5-Methylimidazole alkane-2, the 4-diketone
LC-MS(APCI)m/z?386/388?3∶1(MH+).
1H?NMR(DMSO-d 6)：δ10.73(1H，s)；8.01(1H，s)；7.36-7.28(4H，m)；3.66-3.54(2H，m)；3.51，3.33(1?H?each，ABq，J＝14.9Hz)；2.92-2.80(2H，m)；2.67-2.58(1H，m)；1.81(2H，br?d)；1.68-1.56(2H，m)；1.33(3H，s).
(5S)-and 5-methyl-5-{[(4-tetramethyleneimine-1-phenylpiperidines-1-yl) alkylsulfonyl] methyl } imidazolidine-2, the 4-diketone Trifluoroacetic acid
LC-MS(APCI)m/z?345(MH+).
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；9.61(1H，br?s)；8.01(1H，s)；3.60(2H，t)；3.51，3.36(1H?each，ABq，J＝14.8Hz)；3.55-3.47(2H，m)；3.27-3.15(1H，m)；3.13-3.02(2H，m)；2.80(2H，t)；2.12(2H，br?d)；2.07-1.94(2H，m)；1.86-1.77(2H，m)；1.62-1.49(2H，m)；1.32(3H，s).
19F?NMR(DMSO-d 6)：δ-74.02
(5S)-5-methyl-5-({ [4-(tetrahydrofuran (THF)-2-base carbonyl) piperazine-1-yl] alkylsulfonyl } methyl) imidazolidine -2, the 4-diketone
LC-MS(APCI)m/z?375(MH+).
1H?NMR(DMSO-d 6)：δ10.73(1H，s)；8.01(1H，s)；4.65(1H，dd)；3.80-3.68(2H，m)；3.60-3.42(3H?and?water，m)；3.33(1H，half?ABq，J＝14.9Hz)；3.19-3.00(4H，m)；2.09-1.92(2H，m)；1.87-1.75(2H，m)；1.30(3H，s).
N-[1-([(4S)-and 4-methyl-2,5-dioxo alkyl imidazole-4-yl] methyl } alkylsulfonyl) piperidin-4-yl] benzene Methane amide
LC-MS(APCI)m/z?395(MH+).
1H?NMR(DMSO-d 6)：δ10.72(1H，s)；8.30(1H，d)；8.01(1H，s)；7.82(2H，d)；7.51(1H，t)；7.45(2H，t)；3.96-3.85(1H，m)；3.52(2H，t)；3.50，3.32(1H?each，ABq，J＝14.7Hz)；2.92(2H，t)；1.88(2H，d)；1.55(2H，q)；1.33(3H，s).
(5S)-and 5-{[(4-{[2-(1, the 1-dimethyl ethyl)-1H-indoles-5-yl] amino } piperidines-1-yl) alkylsulfonyl] Methyl }-5-Methylimidazole alkane-2, the 4-diketone
LC-MS(APCI)m/z?462(MH+).
1H?NMR(DMSO-d 6)：δ10.72(1H，s)；10.37(1H，s)；8.00(1H，s)；7.02(1H，d，J＝8.4Hz)；6.58(1H，s)；6.45(1H，d，J＝8.4Hz)；5.86(1H，s)；4.65(1H，Br?s)；3.48，3.29(1H?each，ABq，J＝14.7Hz)；3.46(2H，t)；2.93(2H，t)；1.95(2H，t)；1.45-1.35(2H，m)；1.33(3H，s)；1.29(9H，s).
(5S)-and 5-methyl-5-[(piperidines-1-base alkylsulfonyl) methyl] imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?276(MH+).
1H?NMR(DMSO-d 6)：δ10.70(1H，s)；7.97(1H，s)；3.44，3.23(1H?each，ABq，J＝14.8Hz)；3.13-3.01(4H，m)；1.58-1.42(6H，m)；1.30(3H，s).
(5S)-and 5-[(3,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl]-5-Methylimidazole alkane-2, the 4-diketone
LC-MS(APCI)m/z?274(MH+).
1H?NMR(DMSO-d 6)：δ10.72(1H，s)；8.00(1H，s)；5.85-5.78(1H，m)；5.74-5.68(1H，m)；3.67-3.62(2H，m)；3.47，3.33(1H?each，ABq，J＝14.7Hz)；3.22(2H，dd)；2.14-2.10(2H，m)；1.31(3H，s).
(5S)-5-methyl-5-({ [4-(2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) piperidines-1-yl] sulphonyl Base } methyl) imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?408(MH+).
1H?NMR(DMSO-d 6)：δ10.86(1H，s)；10.75(1H，s)；8.02(1H，s)；7.27-7.17(1H，m)；7.05-6.91(3H，m)；4.38-4.20(1H，m)；3.65(2H，t)；3.56，3.38(1H?each，ABq，J＝14.8Hz)；3.03-2.90(2H，m)；2.41-2.24(2H，m)；1.76(2H，d)；1.34(3H，s).
(5S)-5-({ [4-(1H-1,2,3-benzotriazole-1-yl) piperidines-1-yl] alkylsulfonyl } methyl)-5-methyl miaow Azoles alkane-2, the 4-diketone
LC-MS(APCI)m/z?393(MH+).
1H?NMR(DMSO-d 6)：δ10.77(1H，s)；8.05(1H，s)；8.05(1H，d)；7.93(1H，d)；7.56(1H，t)；7.41(1H，t)；5.12-4.97(1H，m)；3.71(2H，t)；3.58，3.43(1H?each，ABq，J＝14.7Hz)；3.19-3.03(2H，m)；2.29-2.16(4H，m)；1.35(3H，s).
(5S)-5-methyl-5-({ [4-(pyridine-2-ethyl-acetylene base)-3,6-dihydropyridine-1 (2H)-yl] alkylsulfonyl } first Base) imidazolidine-2,4-diketone trifluoroacetic acid
LC-MS(APCI)m/z?375(MH+).
1H?NMR(DMSO-d 6)：δ10.57(1H，s)；8.56(1H，d)；8.03(1H，s)；7.82(1H，t)；7.53(1H，d)；7.38(1H，dd)；6.31(1H，br?s)；3.83(2H，d)；3.54，3.41(1Heach，ABq，J＝14.8Hz)；3.36-3.25(2H，m)；2.42-2.34(2H，m)；1.32(3H，s).
19F?NMR(DMSO-d 6)：δ-75.10
(5S)-5-methyl-5-([the 4-[(4-aminomethyl phenyl) ethynyl]-3,6-dihydropyridine-1 (2H)-yl] alkylsulfonyl } Methyl) imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?388(MH+).
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；8.02(1H，s)；7.32(2H，d)；7.19(2H，d)；6.17(1H，br?s)；3.80(2H，d)；3.52，3.39(1H?each，ABq，J＝14.8Hz)；3.29(2H，t)；2.39-2.32(2H，m)；2.30(3H，s)；1.32(3H，s).
(5S)-5-([the 4-[(4-chloro-phenyl-) ethynyl]-3,6-dihydropyridine-1 (2H)-yl] alkylsulfonyl } methyl)-5- Methylimidazole alkane-2, the 4-diketone
LC-MS(APCI)m/z?408(MH+).
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；8.02(1H，s)；7.54-7.38(4H，m)；6.23(1H，br?s)；3.87-3.76(2H，m)；3.53，3.41(1H?each，ABq，J＝14.9Hz)；3.34-2.25(2H，m)；2.42-2.29(2H，m)；1.32(3H，s).
(5S)-5-[4-(3,4-two chloro-phenoxy groups)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2,4-two Ketone
LC-MS(APCI)m/z(APCI)m/z?436.1(MH+).
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；8.01(1H，s)；7.53(1H，d，J＝9.2Hz)；7.31(1H，d，J＝2.9Hz)；7.02(1H，dd，J＝9.2，2.9Hz)；4.65-4.57(1H，m)；3.51，3.34(1H?each，ABq，J＝15.2Hz)；3.39-3.27(2H，m)；3.17-3.08(2H，m)；2.00-1.90(2H，m)；1.75-1.65(2H，m)；1.33(3H，s).
(5S)-5-[4-(5-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2,4- Diketone
LC-MS(APCI)m/z?403.3(MH+).
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；8.20(1H，d，J＝2.7Hz)；7.81(1H，dd，J＝8.7，2.7Hz)；6.87(1H，d，J＝2.7Hz)；5.16-5.03(1H，m)；3.52，3.35(1Heach，ABq，J＝15.0Hz)；3.43-3.28(2H，m)；3.19-3.07(2H，m)；2.08-1.95(2H，m)；1.80-1.65(2H，m)；1.33(3H，s).
(5S)-5-methyl-5-[4-(5-trifluoromethyl-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-imidazoles Alkane-2, the 4-diketone
LC-MS(APCI)m/z?437(MH+).
1H?NMR(CDCl 3)：δ8.95(1H，s)；8.42-8.38(1H，m)；7.79(1H，dd，J＝8.8，2.5Hz)；6.81(1H，d，J＝8.8Hz)；6.71(1H，s)；5.40-5.28(1H，m)；3.52-3.39(2H，m)；3.40-3.28(2H，m)；3.32(2H，ABq，J＝24.6，14.0Hz)；2.16-2.02(2H，m)；2.02-1.84(2H，m)；1.67(3H，s).
6-[1-((4S)-4-methyl-2,5-dioxo-imidazolidine-4-methylmethane alkylsulfonyl)-piperidin-4-yl oxygen base]-The nicotinic acid nitrile ( Nicotinonitrile)
LC-MS(APCI)m/z?394.3(MH+).
1H?NMR(DMSO-d 6)：δ10.72(1H，s)；8.68(1H，d，J＝2.3Hz)；8.14(1H，dd，J＝8.7，2.3Hz)；8.00(1H，s)；6.98(1H，d，J＝8.7Hz)；5.27-5.14(1H，m)；3.56-3.28(4H，m)；3.18-3.06(2H，m)；2.08-1.96(2H，m)；1.81-1.66(2H，m)；1.31(3H，s).
(5S)-and 5-methyl-5-(4-p-tolyloxy-piperidines-1-alkylsulfonyl methyl)-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?382.5(MH+).
1H?NMR(DMSO-d 6)：δ10.73(1H，s)；8.01(1H，s)；7.09(2H，d，J＝8.4Hz)；6.87(2H，d，J＝8.4Hz)；4.50-4.42(1H，m)；3.50，3.34(1H?each，ABq，J＝14.8Hz)；3.38-3.29(2H，m)；3.17-3.09(2H，m)；2.23(3H，s)；1.99-1.89(2H，m)；1.73-1.63(2H，m)；1.33(3H，s).
(5S)-5-methyl-5-[4-(4-trifluoromethyl-phenoxy group)-piperidines-1-alkylsulfonyl methyl]-imidazolidine-2,4- Diketone
LC-MS(APCI)m/z?436.3(MH+).
1H?NMR(DMSO-d 6)：δ10.71(1H，brs)；8.02(1H，s)；7.65(2H，d，J＝8.8Hz)；7.17(2H，d，J＝8.8Hz)；4.72-4.64(1H，m)；3.52，3.35(1H?each，ABq，J＝14.7Hz)；3.40-3.28(2H，m)；3.19-3.10(2H，m)；2.05-1.95(2H，m)；1.78-1.68(2H，m)；1.33(3H，s).
4-[1-(4S)-4-methyl-2,5-dioxo-imidazolidine-4-methylmethane alkylsulfonyl)-piperidin-4-yl oxygen base]- Benzonitrile
LC-MS(APCI)M/Z?393.2(MH+).
1H?NMR(DMSO-d 6)：δ10.73(1H，s)；8.00(1H，s)；7.76(2H，d，J＝8.8Hz)；7.15(2H，d，J＝8.8Hz)；4.74-4.65(1H，m)；3.51，3.34(1H?each，ABq，J＝14.9Hz)；3.40-3.27(2H，m)；3.17-3.07(2H，m)；2.03-1.94(2H，m)；1.77-1.66(2H，m)；1.32(3H，s).
(5S)-5-[4-(4-methoxyl group-phenoxy group)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2,4-two Ketone
LC-MS(APCI)m/z?398.2(MH+).
1H?NMR(DMSO-d 6)：δ10.73(1H，s)；8.01(1H，s)；6.89(4H，ABq，J＝29.1，9.1Hz)；4.43-4.34(1H，m)；3.70(3H，m)；3.51，3.33(1H，ABq，J＝15.0Hz)；3.38-3.28(2H，m)；3.16-3.05(2H，m)；1.97-1.87(2H，m)；1.73-1.62(2H，m)；1.33(3H，s).
(5S)-5-[4-(3,4-two fluoro-phenoxy groups)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2,4-two Ketone
LC-MS(APCI)m/z?404.2(MH+).
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；8.01(1H，s)；7.35(1H，q，J＝19.6，9.2Hz)；7.19-7.11(1H，m)；6.86-6.80(1H，m)；4.57-4.48(1H，m)；3.51，3.34(1H?each，ABq，J＝14.9Hz)；3.38-3.28(2H，m)；2.16-2.06(2H，m)；2.00-1.90(2H，m)；1.74-1.64(2H，m)；1.33(3H，s).
(5S)-5-[4-(4-chloro-phenoxy group)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?402(MH+).
1H?NMR(DMSO-d 6)：δ10.73(1H，s)；8.00(1H，s)；7.32(2H，d，J＝8.8Hz)；7.00(2H，d，J＝8.8Hz)；4.56-4.48(1H，m)；3.50，3.33(1H?each，ABq，J＝14.8Hz)；3.37-3.28(2H，m)；3.16-3.06(2H，m)；2.00-1.90(2H，m)；1.73-1.63(2H，m)；1.32(3H，s).
(5S)-5-[4-(5-ethyl-pyrimidine-2-yloxy)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2, The 4-diketone
LC-MS(APCI)m/z?398(MH+).
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；8.47(2H，s)；8.02(1H，s)；5.11-5.03(1H，m)；3.52，3.35(1H?each，ABq，J＝14.8Hz)；3.42-3.28(2H，m)；3.19-3.10(2H，m)；2.54(2H，q，J＝15.2，7.6Hz)；2.06-1.98(2H，m)；1.81-1.71(2H，m)；1.33(3H，s)；1.17(3H，t，J＝7.2Hz).
(5S)-5-methyl-5-[4-(4-trifluoromethyl-pyrimidine-2-yloxy)-piperidines-1-alkylsulfonyl methyl]-imidazoles Alkane-2, the 4-diketone
LC-MS(APCI)m/z?438(MH+).
1H?NMR(CDCl 3)：δ8.84-8.76(1H，m)；8.02(1H，s)；7.31(1H，d，J＝4.8Hz)；6.33(1H，s)；5.41-5.34(1H，m)；4.54-4.42(4H，m)；3.35，3.24(1H?each，ABq，J＝12.9Hz)；2.17-2.07(4H，m)；2.02(3H，s).
(5S)-5-methyl-5-[4-(5-methyl-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-imidazolidine-2, The 4-diketone
LC-MS(APCI)m/z?383(MH+).
1H?NMR(CDCl 3)：δ8.14(1H，s)；8.06-7.99(2H，m)；7.19(1H，s)；7.09(1H，d，J＝11.6Hz)；5.28-5.21(1H，m)；3.70-3.41(6H，m)；2.44(3H，s)；2.13-1.96(4H，m)；1.62(3H，s).
(5S)-5-[4-(4-fluoro-benzoyl)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?398(MH+).
1H?NMR(DMSO-d 6)：δ8.06(2H，q，J＝9.2，6.0Hz)；7.40(2H，t，J＝8.8Hz)；3.61-3.41(4H，m)；3.00-2.91(2H，m)；1.90-1.81(2H，m)；1.62-1.50(2H，m)；1.33(3H，s).
(5S)-5-[4-(5-fluoro-pyrimidine-2-yloxy)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2,4- Diketone
LC-MS(APCI)m/z?388(MH+).
1H?NMR(CDCl 3)：δ8.42(2H，s)；8.30(1H，s)；6.40(1H，s)；5.30-5.23(1H，m)；3.53-3.35(4H，m)；3.36，3.21(1H?each，ABq，J＝14.4Hz)；2.10-2.02(4H，m)；1.70(3H，s).
(5S)-5-[4-(6-methoxyl group-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine -2, the 4-diketone
LC-MS(APCI)m/z?399(MH+).
1H?NMR(MeOD)：δ7.54(1H，t，J＝8.4Hz)；6.33-6.28(2H，m)；5.24-5.14(1H，m)；3.86(3H，s)；3.53-3.42(2H，m)；3.58，3.39(1H?each，ABq，J＝14.4Hz)；3.30-3.22(2H，m)；2.13-2.02(2H，m)；1.96-1.82(2H，m)；1.47(3H，s).
(5S)-5-[4-(6-chloro-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2,4- Diketone
LC-MS(APCI)m/z?403(MH+).
1H?NMR(MeOD)：δ7.65(1?H，t，J＝7.8Hz)；6.97(1H，d，J＝7.2Hz)；6.73(1H，d，J＝7.2Hz)；5.25-5.14(1H，m)；3.55-3.44(2H，m)；3.58，3.39(1H?each，ABq，J＝14.4Hz)；3.28-3.19(2H，m)；2.14-2.02(2H，m)；1.92-1.79(2H，m)；1.47(3H，s).
3-[1-((4S)-4-methyl-2,5-dioxo-imidazolidine-4-methylmethane alkylsulfonyl)-piperidin-4-yl oxygen base]- Benzonitrile
LC-MS(APCI)m/z?393(MH+).
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；8.02(1H，s)；7.52-7.47(2H，m)；7.42-7.38(1H，m)；7.36-7.31(1H，m)；4.69-4.61(1H，m)；3.52，3.35(1H?each，ABq，J＝17.2Hz)；3.18-3.07(2H，m)；2.02-1.95(2H，m)；1.79-1.65(2H，m)；1.33(3H，s).
(5S)-5-[4-(3-methoxyl group-phenoxy group)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2,4-two Ketone
LC-MS(APCI)m/z?398(MH+).
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；8.01(1H，s)；7.21-7.15(1H，m)；6.58-6.50(3H，m)；4.57-4.49(1H，m)；3.73(3H，s)；3.51，3.34(1H?each，ABq，J＝14.4Hz)；3.17-3.08(2H，m)；2.01-1.91(2H，m)；1.74-1.64(2H，m)；1.33(3H，s).
N-{4-[1-((4S)-4-methyl-2,5-dioxo-imidazolidine-4-methylmethane alkylsulfonyl)-piperidin-4-yl oxygen Base]-phenyl }-ethanamide
LC-MS(APCI)m/z?425(MH+).
1H?NMR(DMSO-d 6)：δ10.69(1H，brs)；9.78(1H，s)；8.00(1H，s)；7.47(2H，d，J＝9.2Hz)；6.91(2H，d，J＝9.2Hz)；4.48-4.41(1H，m)；3.51(1H?from?ABq，J＝14.4Hz)；3.16-3.06(2H，m)；2.00(3H，s)；1.98-1.90(2H，m)；1.73-1.63(2H，m)；1.33(3H，s).
(5S)-5-[4-(3-chloro-phenoxy group)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?402(MH+).
1H?NMR(DMSO-d 6)：δ10.76(1H，brs)；7.99(1H，s)；7.31(1H，t，J＝8.4Hz)；7.08(1H，t，J＝2.2Hz)；7.02-6.95(2H，m)；4.64-4.56(1H，m)；3.51(1Hfrom?ABq，J＝14.4Hz)；3.17-3.09(2H，m)；2.00-1.91(2H，m)；1.75-1.65(2H，m)；1.33(3H，s).
(5S)-5-methyl-5-[4-(4-trifluoromethoxy-phenoxy group)-piperidines-1-alkylsulfonyl methyl]-imidazolidine-2, The 4-diketone
LC-MS(APCI)m/z?452(MH+).
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；8.01(1H，s)；7.29(2H，d，J＝8.8Hz)；7.08(2H，d，J＝9.2Hz)；4.60-4.52(1H，m)；3.51(1H?from?ABq，J＝14.8Hz)；3.17-3.08(2H，m)；2.02-1.93(2H，m)；1.75-1.65(2H，m)；1.33(3H，s).
(5S)-5-methyl-5-[4-(3-trifluoromethoxy-phenoxy group)-piperidines-1-alkylsulfonyl methyl]-imidazolidine-2, The 4-diketone
LC-MS(APCI)m/z?452(MH+).
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；8.01(1H，s)；7.41(1H，t，J＝8.4Hz)；7.06-6.91(3H，m)；4.65-4.58(1H，m)；3.51(1H?from?ABq，J＝14.8Hz)；3.18-3.08(2H，m)；2.02-1.93(2H，m)；1.76-1.65(2H，m)；1.33(3H，s).
(5S)-5-[4-(2,4-two fluoro-phenoxy groups)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2,4-two Ketone
LC-MS(APCI)m/z?404(MH+).
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；8.02(1H，s)；7.34-7.23(2H，m)；7.06-6.97(1H，m)；4.50-4.41(1H，m)；3.50(1H?from?ABq)；3.17-3.06(2H，m)；2.02-1.90(2H，m)；1.78-1.65(2H，m)；1.33(3H，s).
(5S)-5-[4-(4-fluoro-phenoxy group)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?386(MH+).
1H?NMR(DMSO-d 6)：δ10.75(1H，s)；8.02(1H，s)；7.17-6.97(2H，m)；4.52-4.43(1H，m)；3.17-3.06(2H，m)；2.00-1.89(2H，m)；1.75-1.62(2H，m)；1.33(3H，s).
(5S)-5-[4-(3-fluoro-phenoxy group)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?386(MH+).
1H?NMR(DMSO-d 6)：δ10.72(1H，s)；8.02(1H，s)；7.36-7.26(1H，m)；6.91-6.71(3H，m)；4.62-4.52(1H，m)；3.18-3.06(2H，m)；2.02-1.91(2H，m)；1.78-1.63(2H，m)；1.33(3H，s).
(5S)-5-[4-(2-fluoro-phenoxy group)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?386(MH+).
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；8.01(1H，s)；7.28-7.17(2H，m)；7.17-7.08(1H，m)；7.02-6.97(1H，m)；4.59-4.47(1H，m)；2.04-1.92(2H，m)；1.80-1.67(2H，m)；1.33(3H，s).
(5S)-5-[4-(5-methoxyl group-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine -2, the 4-diketone
LC-MS(APCI)m/z?399(MH+)。
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；8.01(1H，s)；7.89(1H，d，J＝3.16Hz)；7.39(1H，dd，J＝3.18，9.07Hz)；6.77(1H，d，J＝8.95Hz)；5.08-4.96(1H，m)；3.76(3H，s)；3.51，3.34(1H?each，ABq，J＝14.7Hz)；3.43-3.29(2H，m)；3.18-3.05(2H，m)；2.05-1.94(2H，m)；1.77-1.61(2H，m)；1.33(3H，s).
(5S)-5-methyl-5-[4-(4-pyridin-3-yl-phenyl)-piperazine-1-alkylsulfonyl methyl]-imidazolidine-2,4-two Ketone
LC-MS(APCI)m/z?430(MH+)。
1H?NMR(DMSO-d 6)：δ10.76(1H，s)；8.99(1H，s)；8.60(1H，d，J＝4.91Hz)；8.35(1H，d，J＝7.81Hz)；8.04(1H，s)；7.70(2H，d，J＝8.87Hz)；7.12(2H，d，J＝8.91Hz)；3.57(1H?from?ABq)；3.35(4H，m)；3.27(4H，m)；1.33(3H，s).
(5S)-and 5-methyl-5-({ [4-(pyridine-2-base oxygen base) piperidines-1-yl] alkylsulfonyl } methyl) imidazolidine-2,4- Diketone
LC-MS(APCI)m/z?369(MH+).
1H?NMR(CDCl 3)：δ1.73(3H，s)；1.96-2.04(2H，m)；2.04-2.13(2H，m)；3.21(1H，d)；3.36-3.42(3H，m)；3.45-3.50(2H，m)；5.29-5.33(1H，m)；6.30(1H，bs)；6.78(1H，d)；6.93(1H，t)；7.65(1H，t)；7.70(1H，bs)；8.16(1H，d).
(5S)-and 5-[({4-[(3, the 4-dimethyl benzyl) the oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-the 5-Methylimidazole Alkane-2, the 4-diketone
(NB. contains 30%2,3-dimethyl isomer, it is an initial substance)
LC-MS(APCI)m/z?410(M+)。
1H?NMR(DMSO-d 6)：δ1.3(3H，s)；1.53-1.64(2H，m)；1.83-1.89(2H，m)；2.18(3H，s)；2.20(3H，s)；2.95-3.33(2H，m)；3.25-3.31(3H，m)；3.45(1H，d)；3.45-3.53(1H，m)；4.42(2H，s)；7.01-7.15(3H，m)；7.97(1H，s)；10.70(1H，s).
(5S)-and 5-methyl-5-{[(4-Phenoxypiperidines-1-yl) alkylsulfonyl] methyl } imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?368(MH+)。
1H?NMR(DMSO-d 6)：δ1.30(3H，s)；1.64-1.73(2H，m)；1.92-2.00(2H，m)；3.08-3.15(2H，m)；3.28-3.44(4H，m)；4.49-4.54(1H，m)；6.92(1H，t)；6.96(2H，d)；7.28(2H，t)；7.69(1H，bs)；10.7(1H，bs).
4-fluoro-N-[1-((4S)-4-methyl-2,5-dioxo-imidazolidine-4-methylmethane alkylsulfonyl)-piperidin-4-yl]- Benzamide
LC-MS(APCI)m/z?413(MH+)。
1H?NMR(DMSO-d 6)：δ10.73(1H，s)；8.34(1H，d，J＝7.50Hz)；8.02(1H，s)；7.94-7.88(2H，m)；7.33-7.26(2H，m)；3.96-3.86(1H，m)；3.58-3.47(2H，m)；3.51，3.32(1H?each，ABq，J＝14.81Hz)；2.97-2.88(2H，m)；1.92-1.84(2H，m)；1.62-1.48(2H，m)；1.33(3H，s).
(5S)-and 5-[({4-[(2, the 5-dimethyl benzyl) the oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-the 5-Methylimidazole Alkane-2, the 4-diketone
LC-MS(APCI)m/z?410(MH+).
1H?NMR(DMSO-d 6)：δ1.30(3H，s)；1.54-1.62(2H，m)；1.85-1.91(2H，m)；2.21(3H，s)；2.24(3H，s)；2.97-3.03(2H，m)；3.27-3.34(3H，m)；3.45(1H，d)；3.49-3.55(1H，m)；6.97-7.04(2H，m)；7.11(1H，s)；7.98(1H，s)；10.70(1H，s).
(5S)-and 5-{[4-(5-chloropyridine-2-yl) piperidines-1-yl] alkylsulfonyl }-5-Methylimidazole alkane-2, the 4-diketone
LC-MS(APCI)m/z?387(MH+).
1H?NMR(DMSO-d 6)：δ10.72(1H，s)；8.54(1H，d)；8.01(1H，s)；7.86(1H，dd)；7.38(1H，d)；3.61(2H，bt)；3.50，3.32(1H?each，ABq，J＝14.9Hz)；2.96-2.76(3H，m)；1.92(2H，brd)；1.77-1.62(2H，m)；1.33(3H，s).
(5S)-5-[4-(5-benzyloxy-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine -2, the 4-diketone
LC-MS(APCI)m/z?475(MH+)。
1H?NMR(DMSO-d 6)：δ10.73(1H，s)；8.01(1H，s)；7.90(1H，d，J＝3.13Hz)；7.48-7.30(6H，m)；6.76(1H，d，J＝8.97Hz)；5.10(2H，s)；5.05-4.98(1H，m)；3.51(1H(from?ABq)，J＝14.84Hz)；3.40-3.30(3H，m)；3.15-3.07(2H，m)；2.07-1.95(2H，m)；1.74-1.64(2H，m)；1.33(3H，s).
(5S)-5-[4-(6-chloro-pyridin-3-yl oxygen base)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2,4- Diketone
LC-MS(APCI)m/z?403(MH+)。
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；8.17(1H，d，J＝3.10Hz)；8.01(1H，s)；7.56(1H，dd，J＝3.18，8.80Hz)；7.44(1H，d，J＝8.77Hz)；4.67-4.59(1H，m)；3.52，3.35(2H，ABq，J＝15.22Hz)；3.39-3.28(2H，m)；3.17-3.08(2H，m)；2.03-1.93(2H，m)；1.77-1.67(2H，m)；1.33(3H，s).
(5S)-5-[4-(5-hydroxyl-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2, The 4-diketone
LC-MS(APCI)m/z?385(MH+)。
1H NMR (methyl alcohol-d 4): δ 7.73 (1H, d, J=3.01Hz); 7.53 (1H, dd, J=3.11,9.03Hz); 7.04 (1H, d, J=9.04Hz); 3.80-3.67 (1H, m); 3.58,3.41 (2H, ABq, J=15.04Hz); 3.53-3.42 (2H, m); 3.36-3.18 (2H, m); 2.17-2.02 (2H, m); 1.96-1.81 (2H, m); 1.48 (3H, s).
(5S)-5-[4-(4-chloro-phenyl sulfenyl (sulfanyl))-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine -2, the 4-diketone
LC-MS(APCI)m/z?418(MH+).
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；8.00(1H，s)；7.45-7.39(4H，m)；2.97-2.89(2H，m)；2.00-1.91(2H，m)；1.56-1.45(2H，m)；1.31(3H，s).
(5S)-5-[4-(4-chloro-benzenesulfonyl)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?450(MH+)。
1H?NMR(DMSO-d 6)：δ10.73(1H，s)；7.99(1H，s)；7.86(2H，d，J＝8.77Hz)；7.77(2H，d，J＝8.75Hz)；3.66-3.54(2H，m)；3.50-3.41(1H，m)；3.44，3.32(1Heach，ABq，J＝14.63Hz)；2.82-2.73(2H，m)；1.97-1.88(2H，m)；1.57-1.42(2H，m)；1.30(3H，s).
(5S)-5-[4-(4-fluoro-phenyl amino)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?385(MH+)。
1H NMR (methyl alcohol-d 4): δ 7.20-7.11 (4H, m); 3.84-3.71 (2H, m); 3.60-3.48 (1H, m); 3.56,3.39 (1H each, ABq, J=14.96Hz); 2.97-2.84 (2H, m); 2.10-2.00 (2H, m); 1.69-1.53 (2H, m); 1.46 (3H, s).
N-{3-[1-((4S)-4-methyl-2,5-dioxo-imidazolidine-4-methylmethane alkylsulfonyl)-piperidin-4-yl oxygen Base]-phenyl }-ethanamide
LC-MS(APCI)m/z?425(MH+)。
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；9.89(1H，s)；8.01(1H，s)；7.37-7.33(1H，m)；7.21-7.14(1H，m)；7.08-7.03(1H，m)；6.65(1H，dd，J＝1.89，8.04Hz)；4.49-4.42(1H，m)；3.5?1，3.34(1H?each，ABq，J＝14.73Hz)；3.39-3.28(2H，m)；3.18-3.08(2H，m)；2.02(3H，s)；2.00-1.92(2H，m)；1.76-1.65(2H，m)；1.33(3H，s).
(5S)-5-[4-(4-chloro-benzoyl)-piperazine-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?415(MH+)。
1H?NMR(DMSO-d 6)：δ10.75(1H，s)；8.04(1H，s)；7.54(2H，d，J＝8.38Hz)；7.45(2H，d，J＝8.38Hz)；3.79-3.55(2H，bs)；3.56，3.35(1H?each，ABq，J＝14.84Hz)；3.51-3.31(2H，bs)；3.27-3.06(4H，bs)；1.33(3H，s).
1-((4S)-4-methyl-2,5-dioxo-imidazolidine-4-methylmethane alkylsulfonyl)-piperidines-4-carboxylic acid (4-fluoro- Phenyl)-acid amides
LC-MS(APCI)m/z?413(MH+)。
1H?NMR(DMSO-d 6)：δ10.74(1H，s)；9.97(1H，s)；8.02(1H，s)；7.65-7.58(2H，m)；7.16-7.09(2H，m)；3.62-3.52(2H，m)；3.49，3.33(1H?each，ABq，J＝14.94Hz)；2.87-2.77(2H，m)；2.48-2.39(1H，m)；1.91-1.84(2H，m)；1.70-1.57(2H，m)；1.33(3H，s).
(5S)-5-[4-(5-bromo-pyridine-2-base oxygen base)-piperidines-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2,4- Diketone
LC-MS(APCI)m/z?447，449(MH+)。
1H?NMR(DMSO-d 6)：δ10.73(1H，s)；8.28(1H，d，J＝2.64Hz)；8.01(1H，s)；7.91(1H，dd，J＝2.60，8.84Hz)；6.83(1H，d，J＝8.79Hz)；5.12-5.05(1H，m)；3.52，3.35(1H?each，ABq，J＝14.85Hz)；3.41-3.34(2H，m)；3.17-3.08(2H，m)；2.06-1.97(2H，m)；1.78-1.67(2H，m)；1.33(3H，s).
(5S)-5-[4-(5-(4-fluoro-phenyl)-pyridine-2-yl)-piperazine-1-alkylsulfonyl methyl]-5-methyl-imidazolidine -2, the 4-diketone
LC-MS(APCI)m/z?448(MH+)。
1H?NMR(DMSO-d 6)：δ10.75(1H，s)；8.45(1H，d，J＝2.51Hz)；8.02(1H，s)；7.88(1H，dd，J＝2.57，8.86Hz)；7.70-7.62(2H，m)；7.30-7.22(2H，m)；6.98(1H，d，J＝8.94Hz)；3.70-3.62(4H，m)；3.55，3.36(1H?each，ABq，J＝14.73Hz)；3.26-3.19(4H，m)；1.32(3H，s)
(5S)-5-[4-(5-(4-methoxyl group-phenyl)-pyridine-2-yl)-piperazine-1-alkylsulfonyl methyl]-5-methyl-miaow Azoles alkane-2, the 4-diketone
LC-MS(APCI)m/z?460(MH+).
(5S)-5-[4-(5-(4-chloro-phenyl)-pyridine-2-yl)-piperazine-1-alkylsulfonyl methyl]-5-methyl-imidazolidine -2, the 4-diketone
LC-MS(APCI)m/z?464，466(MH+).
(5S)-5-[4-(5-(4-trifluoromethoxy-phenyl)-pyridine-2-yl)-piperazine-1-alkylsulfonyl methyl]-the 5-first Base-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?514(MH+).
(5S)-5-[4-(5-furans-2-base-pyridine-2-yl)-piperazine-1-alkylsulfonyl methyl]-5-methyl-imidazolidine-2, The 4-diketone
LC-MS(APCI)m/z?420(MH+).
(5S)-5-methyl-5-(4-[5-(1H-pyrroles-2-yl)-pyridine-2-yl]-piperazine-1-alkylsulfonyl methyl)-miaow Azoles alkane-2, the 4-diketone
LC-MS(APCI)m/z?419(MH+).
(5S)-5-(4-[3,3 ']-Bi pyridyl-6-base-piperazine-1-alkylsulfonyl methyl)-5-methyl-imidazolidine-2,4- Diketone
LC-MS(APCI)m/z?431(MH+).
(4S)-4-(6-[4-(4-methyl-2,5-dioxo-imidazolidine-4-methylmethane alkylsulfonyl)-piperazine-1-yl]-pyrrole Pyridine-3-yl)-benzonitrile
LC-MS(APCI)m/z?455(MH+).
Embodiment 19
Compound with following general formula
Figure A0281004101741
Synthetic according to the method for describing among the embodiment 17.
Figure A0281004101742
(1): NMR can obtain, and sees experimental section.
5-[({4-[(5-chloropyridine-2-yl) oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-5-[(3,4,4-trimethylammonium-2, 5-dioxo alkyl imidazole-1-yl) methyl] imidazolidine-2, the 4-diketone
The description that title compound is pressed embodiment 17 is by racemize { 2,5-dioxo-4-[(3,4,4-trimethylammonium-2,5-dioxo alkyl imidazole-1-yl) methyl] imidazolidine-4-yl } methane sulfonyl chloride and 5-chloro-2-(piperidin-4-yl oxygen base)-pyridine preparation.
LC-MS(APCI)m/z?543(MH+).
1H?NMR(DMSO-d 6)：δ1.28(6H，s)；1.63-1.74(2H，m)；1.95-2.05(2H，m)；2.77(3H，s)；3.14(4H，d)；3.53-3.73(3H，m)；4.14(1H，q)；5.04-5.11(1H，m)；6.85(1H，d)；7.80(1H，dd)；7.94(1H，s)；8.19(1H，d)；10.83(1H，s).
Initial substance is by being prepared as follows:
3-[3-(dibenzylsulfide)-2-oxopropyl]-1,5,5-tri-methylimidazolium alkane-2,4-diketone
(256 μ l, 2.2mmol) (712mg 2.2mmol) at room temperature stirred 1 hour in dimethyl formamide (5ml) with cesium carbonate with benzyl mercaptan.Add and press the 3-(3-bromo-2-oxopropyl)-1,5 that WO99/06361 prepares, 5-tri-methylimidazolium alkane-2, (552mg 1.99mmol), and at room temperature stirred this this mixture 18 hours the 4-diketone.With this reaction mixture water treatment, be extracted into ethyl diacetate and (in 3 * 25ml), organic phase merged, with salt water washing and dry.This product by silica gel chromatography purifying (with 50% ethyl diacetate/isohexane wash-out), is obtained the 300mg product.
LC-MS(APCI)m/z?321(MH+).
1H?NMR(CDCl 3)：δ1.45(6H，s)；2.91(3H，s)；3.16(2H，s)；3.70(2H，s)；4.53(2H，s)；7.22-7.33(5H，m).
The 5-[(dibenzylsulfide) methyl]-5-[(3,4,4-trimethylammonium-2,5-dioxo alkyl imidazole-1-yl) methyl] imidazoles Alkane-2, the 4-diketone
Press synthetic 5-methyl-5-{[(phenmethyl among the embodiment 17) sulphur] methyl } imidazolidine-2, the description in the 4-diketone prepares title compound.
LC-MS(APCI)m/z?391(MH+)。
1H?NMR(DMSO-d 6)：δ1.28(6H，s)；2.64?and?2.76(2H，abq，J＝14.2Hz)；2.78(3H，s)；3.54&3.64(2H，abq，J＝14.2Hz)；3.73(2H，s)；7.20-7.32(5H，m)；7.98(1H，s)；10.83(1H，s).
2,5-dioxo-4-[(3,4,4-trimethylammonium-2,5-dioxo alkyl imidazole-1-yl) and methyl] imidazolidine-4- Base } methane sulfonyl chloride
The description of pressing among the embodiment 17 in synthetic [(4S) and (4R)-4-methyl-2,5-dioxo alkyl imidazole-4-yl] methane sulfonyl chloride prepares title compound.
1H?NMR(CD 3OD)：δ1.38(6H，s)；2.89(3H，s)；3.81?and?3.92(2H，abq，J＝14.3Hz)；4.61(2H，s).
Following compounds is by synthetic 5-[({4-[(5-chloropyridine-2-yl) the oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-5-[(3,4,4-trimethylammonium-2,5-dioxo alkyl imidazole-1-yl) methyl] imidazolidine-2, the description preparation in the 4-diketone.
5-[({4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } alkylsulfonyl) methyl]-5-[(3,4, the 4-front three Base-2,5-dioxo alkyl imidazole-1-yl) methyl] imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?562(MH+)。
1H?NMR(DMSO-d 6)：δ1.26(6H，s)；2.76(3H，s)；3.16-3.22(4H，m)；3.48-3.76(8H，m)；7.02(1H，d)；7.81-7.76(2H，m)；8.43(1H，s)；10.83(1H，s).
5-[4-(4-fluoro-phenyl-Piperazine-1-alkylsulfonyl methyl]-5-[(3,4,4-trimethylammonium-2,5-dioxo imidazoles Alkane-1-yl) methyl] imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?511(MH+).
1H?NMR(DMSO-d 6)：δ1.28(6H，s)；2.77(3H，s)；3.10-3.16(4H，m)；3.21-3.26(4H，m)；3.48-3.71(4H，m)；6.95-7.09(4H，m)；7.88(1H，s)；10.84(1H，bs).
5-[({4-[(5-chloropyridine-2-yl) oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-the 5-{2-[(phenmethyl) the oxygen base] Ethyl } imidazolidine-2, the 4-diketone
Title compound is by synthetic 5-[({4-[(5-chloropyridine-2-yl) the oxygen base] piperidines-1-yl } alkylsulfonyl) methyl]-5-[(3; 4; 4-trimethylammonium-2; 5-dioxo alkyl imidazole-1-yl) methyl] imidazolidine-2; description in the 4-diketone is by 5-chloro-2-(piperidin-4-yl oxygen base)-pyridine hydrochloride and (2,5-dioxo-4-{2-[(phenmethyl) oxygen base] ethyl } imidazolidine-4-yl) the initial preparation of methane sulfonyl chloride.
LC-MS(APCI)m/z?523(MH+).
1H NMR (DMSO-d 6): δ 1.37-1.79 (3H, m); 1.83-2.08 (4H, m); 3.00-3.56 (part is by D for 7H, m 2O shelters); 4.33-4.44 (2H, m); 5.01-5.12 (1H, m); 6.85 (1H, d); 7.21-7.36 (5H, m); 7.80 (1H, dd); 8.02 (1H, s); 8.19 (1H, d); 10.70 (1H, bs).
6-(4-[(5-chloropyridine-2-yl) and the oxygen base] piperidines-1-yl } alkylsulfonyl)-1,3-diaza spiro [4.5] decane-2, The 4-diketone
LC-MS(APCI)m/z?443(MH+).
By being prepared as follows initial substance:
The 6-[(phenmethyl) sulphur]-1,3-diaza spiro [4.5] decane-2,4-diketone
(937mg 7.5mmol) is dissolved among the 70mL of THF with benzyl mercaptan.(362mg 60%, 9.0mmol), and with slurry stirred for several minute to add NaH.(1.0g 7.5mmol), and at room temperature stirs reactant and to spend the night to add 2-chlorine hexanaphthene.Filter out solid and solvent is removed by rotary evaporation.Add potassium cyanate (4eq), (NH4) 2CO 3(8eq) with 25mL ethanol.This reaction mass is spent the night 80 ℃ of following stirrings in the bottle of sealing.With suspension filtered and with solid DMSO and water recrystallization, obtain title compound, be white solid.
LC-MS(APCI)m/z?291(MH+)。
1HNMR(DMSO-d 6)：δ1.21-1.81(8H，m)；2.79(1H，dd)；3.67-3.76(2H，m)；7.18-7.32(5H，m)；8.43(1H，s)；10.68(1H，s).
Embodiment 20
5-methyl-5-(1-(toluene-4-alkylsulfonyl)-cyclopentyl)-imidazolidine-2, the 4-diketone
With 1-(1-(toluene-4-alkylsulfonyl)-cyclopentyl))-ethyl ketone (0.10g, 0.38mmol), potassium cyanide (0.049g; 0.75mmol); (0.18g, 1.9mmol), 50% aqueous ethanolic solution (1.6mL) in water stirred 70 hours down at 90 ℃ in the pipe (2mL volume) of sealing volatile salt.This solution is acidified to pH6 and is concentrated into half of its initial volume by rotatory evaporator with 10% acetate, and this moment, portioned product settled.Solution and its solid phase prod are absorbed as in the ethyl acetate, aqueous phase separation is also used the ethyl acetate washed twice.The organic phase that merges with salt water washing, dry on anhydrous sodium sulphate, is filtered also and concentrated by rotatory evaporator, obtain the 0.74g white solid.Should be dissolved in the methyl alcohol (5mL) by thick product, concentrate (1g) with silicon-dioxide by rotatory evaporator, and impose on the short silicon-dioxide pillar.With ethyl acetate/normal heptane (1: 2 and 2: 1) washing, obtain 0.060g (48%) title compound, be colourless spicule.
LC-MS(APCI)m/z?337(MH+).
1H?NMR(DMSO-d 6)：δ0.96-1.10(1H，m)；1.32-1.44(1H，m)；1.36(3H，s)；1.47-1.58(2H，m)；2.10-2.30(4H，m)；2.40(3H，s)；7.41(2H，d，J＝8Hz)；7.72(2H，d，J＝8Hz)；7.80(1H，bs)and?10.7(1H，bs).
13C?NMR(DMSO-d 6)：δ21.0，22.60，22.64，26.1，26.3，30.8，31.5，64.1，78.9，129.2，130.3，135.3，144.2，156.0?and?176.2.
Initial substance is by being prepared as follows:
1-(toluene-4-alkylsulfonyl)-third-2-ketone is according to Crandall Et Al.J.Org.Chem.1985, (4.2g, 18mmol), (1.0mL, 12mmol), normal-butyl bromination ammonium (0.30g) and water-benzene-acetone 4: 3: 3 (10mL) prepares monochloroacetone (8) 50,1327-1329 by the SPTS dihydrate.Refining and at the enterprising circumstances in which people get things ready for a trip spectrum of thick silicon-dioxide purifying (with ethyl acetate/normal heptane (1: 3 to 1: 2) as elutriant), obtain 2.4g (95%) title product, be oily matter, it leaves standstill post crystallization in refrigerator.
LC-MS(APCI)m/z?213(MH+).
1H?NMR(CDCl 3)：δ2.38(3H，s)；2.42(3H，s)；4.10(2H，s)；7.35(d2H，d，J＝8Hz)；7.74(d，2H，d，J＝8Hz).
13C?NMR(CDCl 3)：δ21.7，31.4，67.7，128.0，129.8，135.5，145.3?and?195.9.
1-(1-(toluene-4-alkylsulfonyl)-cyclopentyl))-ethyl ketone
With 1-(toluene-4-alkylsulfonyl)-third-2-ketone (0.10g, 0.47mmol), 1; 4-two iodo butane (0.068mL; 0.52mmol), (0.14g 1.0mmol) stirred 22 hours down at 50 ℃ (oil bath temperatures) with dry methyl-sulphoxide (0.80mL) fine grainding salt of wormwood.Heating closed and 22 ℃ of following continuously stirring 22 hours.Thick product is absorbed in the ethyl acetate, water (5 * 50mL) and salt solution (1 * 50mL) washing at anhydrous sodium sulfate drying, is filtered also and is concentrated by rotary evaporation.The oily resistates at the long purifying of silicon-dioxide chromatogram (with ethyl acetate/normal heptane (1: 4 to 1: 3)), is obtained 0.10g (80%) title compound, obtain water white oil.
LC-MS(APCI)m/z?267(MH+).
1H?NMR(CDCl 3)：δ1.52(2H，m)；1.77(2H，m)；2.26(2H，m)；2.37(2H，m)；2.42(3H，s)；2.48(3H，s)；7.30(2H，d，J＝8Hz)and?7.60(2H，d，J＝8Hz).
13C?NMR(CDCl 3)：δ21.7，25.4，28.0，31.3，83.9，129.4，129.5，133.2，145.0and?202.5
Embodiment 21
5-(biphenyl-4-base oxygen ylmethyl)-5-ethyl-imidazolidine-2, the 4-diketone
Figure A0281004101792
With 4-hydroxyl-xenyl (84mg, 0.5mmol) be added in 1-bromo-2-butanone in the dry acetone (2.5ml) (0.055ml, 0.55mmol) and Anhydrous potassium carbonate (95mg, 0.69mmol) in.This mixture was at room temperature stirred 2 hours, use ethyl acetate (2.5ml) to absorb then.Supernatant liquid is evaporated.With gained oil in sealed tube with volatile salt (290mg, 3.0mmol) and the potassium cyanide in ethanol (3ml) (79mg 1.2mmol) stirs down at 75 ℃ together and spends the night.At ethyl acetate (20ml), ether (10ml) and water (15ml) go up and saturated ammonium chloride (aqueous solution, 2ml) purifying together with gained solution.Organic phase water (10ml) is washed once again, evaporate with heptane then, (112mg 0.36mmol), is white solid, yield 72% yield to obtain title compound.
1HNMR(300MHz，DMSO-d 6)：δ10.57(1H，bs)；8.00(1H，s)；7.63-7.58(4H，m)；7.43(2H，m)；7.01(2H，d)；4.07(2H，dd)；1.67(2H，m)；0.86(3H，t).
LC-MS(APCI)m/z?311.1(MH+).
Embodiment 22
The compound of following general formula
Figure A0281004101801
It is synthetic to press the method for describing among the embodiment 21.
Figure A0281004101802
Figure A0281004101821
(1): for the NMR data referring to experimental section.
5-[1-(biphenyl-4-base oxygen base)-ethyl]-5-methyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?311.2(MH+).
5-(4 '-cyano group-xenyl-4-base oxygen ylmethyl)-5-ethyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?336.2(MH+).
5-(4 '-chloro-xenyl-4-base oxygen ylmethyl)-5-methyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?331.2(MH+).
5-(4 '-cyano group-xenyl-4-base oxygen ylmethyl)-5-methyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?322.2(MH+).
5-(4 '-cyano group-xenyl-4-base oxygen ylmethyl)-the 5-tertiary butyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?364(MH+).
5-(4 '-cyano group-xenyl-4-base oxygen ylmethyl)-5-phenyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?384(MH+).
5-methyl-5-[4-(4-trifluoromethyl-phenoxy group)-phenoxymethyl]-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?381.4(MH+).
5-(4-cyano group-phenoxymethyl)-5-(3-methoxyl group-phenyl)-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?338.2(MH+).
5-(4-cyano group-phenoxymethyl)-5-(3-bromo-phenyl)-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?386.1(MH+).
5-(4-cyano group-phenoxymethyl)-5-phenyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?308.1(MH+).
5-(4-bromo-phenoxymethyl)-5-(3-methoxyl group-phenyl)-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?393.1(MH+).
5-(4-bromo-phenoxymethyl)-5-(3-bromo-phenyl)-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?442.9(MH+).
5-(4-bromo-phenoxymethyl)-5-phenyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?363.1(MH+).
5-(4-methoxyl group-phenoxymethyl)-5-(3-methoxyl group-phenyl)-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?343.2(MH+).
5-(4-methoxyl group-phenoxymethyl)-5-(3-bromo-phenyl)-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?393.2(MH+).
5-(4-methoxyl group-phenoxymethyl)-5-phenyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?313.2(MH+).
5-(4-methyl-phenoxymethyl)-5-(3-methoxyl group-phenyl)-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?327.1(MH+).
5-(4-methyl-phenoxymethyl)-5-(3-bromo-phenyl)-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?377.1(MH+).
5-(4-methyl-phenoxymethyl)-5-phenyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?297.1(MH+).
5-phenoxymethyl-5-(3-methoxyl group-phenyl)-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?313.2(MH+).
5-phenoxymethyl-5-(3-bromo-phenyl)-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?363(MH+).
5-phenoxymethyl-5-phenyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?283.2(MH+).
6-(4-chloro-phenoxy group)-1,3-diaza-spiro [4,4] nonane-2,4-diketone
LC-MS(APCI)m/z?281(MH+).
5-methyl-5-[(4-thiophene phenol-2-base-phenoxymethyl)-and imidazolidine-2, the 4-diketone
With 1-(4-thiophene-2-phenoxyl) acetone (114mg, 0.49mmol), sodium cyanide (40mg, 0.81mmol), volatile salt (222mg, 2.85mmol), water (5ml) and ethanol mixes and be incorporated in 80 ℃ of heating 10 hours down.After the cooling,, solid is leached and drying, obtain the 105mg product this reaction mixture water treatment.
LC-MS(APCI)m/z?303(MH+)。
1H?NMR(DMSO-d 6)：δ1.31(3H，s)；3.95，4.10(2H，abq，J＝9.8Hz)；6.95(2H，d)；7.08(1H，dd)；7.37(1H，d)；7.45(1H，d)；7.55(2H，d)；8.03(1H，s).
By being prepared as follows initial substance:
1-(4-iodo phenoxy group) acetone
(4.9g, 22mmol) (4.7g, 33mmol), (4.5ml, 55mmol) acetone stirred 18 hours under refluxing monochloroacetone together with salt of wormwood with 4-iodo phenol.This reaction mixture is poured in the water (100mL), and (3 * 50mL) extractions, with extract salt water washing, drying is also evaporated on sodium sulfate with ethyl diacetate.Resistates is passed through flash chromatography (using the methylene dichloride wash-out) purifying.
LC-MS(APCI)m/z?275(MH+)。
1H?NMR(CDCl 3)：δ2.26(3H，s)；4.51(2H，s)；6.65(2H，d)；7.57(2H，d).
1-(4-thiophene-2-phenoxyl) acetone
With 1-(4-iodo phenoxy group) acetone (192mg, 0.69mmol) usefulness thiophene phenol-2-boric acid (102mg, 0.79mmol), [1,1 '-two (diphenylphosphine) ferrocene] cooperate (36mg) of dichloro palladium (II) and methylene dichloride (1: 1) handle, dimethyl formamide (12mL) and ammonium acetate (135mg) stirred under 80 ℃ 3 hours together.After the cooling, this reaction mixture is handled and extracted as in the ethyl acetate with dilute hydrochloric acid.(use 50% ethyl diacetate: the purifying isohexane wash-out) obtains the 114mg product by the silicon-dioxide flash chromatography with this product.
LC-MS(APCI)m/z?232(MH+).
Following compound is according to synthetic 5-methyl-5-[(4-thiophene-2-phenoxyl) methyl] imidazolidine-2, the description preparation in the 4-diketone
5-methyl-5-(4 '-(trifluoromethyl-xenyl-4-base oxygen ylmethyl)-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?365(MH+).
1H?NMR(DMSO-d 6)：δ1.46(3H，s)；4.05，4.22(2H，ABq，J＝9.9Hz)；7.04(2H，d)；7.61(2H，d)；7.04，7.61(4H，ABq，J＝9.8Hz).
5-(4 '-(methoxyl group-xenyl-4-base oxygen ylmethyl)-5-methyl-imidazolidine-2, the 4-diketoneLC-MS (APCI) m/z 326 (MH+).
5-(4 '-(fluoro-xenyl-4-base oxygen ylmethyl)-5-methyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?315(MH+)。
1H?NMR(DMSO-d 6)：δ1，45(3H，s)；4.02，4.20(2H，abq，J＝9.9Hz)；6.99(2H，d)；7.12(2H，t)；7.50(2H，d)；7.55(2H，dd)。
N-[4 '-(4-methyl-2,5-dioxo-imidazolidine-4-ylmethoxy)-xenyl-3-yl]-ethanamide
LC-MS(APCI)m/z?354(MH+).
1H?NMR(DMSO-d 6)：δ1.46(3H，s)；2.14(3H，s)；2.15(1H，s)；4.05，4.20(2H，abq，J＝9.6Hz)；7.00(2H，d)；7.28-7.40(3H，m)；7.46(1H，bd)；7.53(2H，d)；7.78-7.81(1H，m)。
5-(3 '-(methoxyl group-xenyl-4-base oxygen ylmethyl)-5-methyl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?327(MH+).
1H?NMR(DMSO-d 6)：δ1.45(3H，s)；3.83(3H，s)；4.04，4.20(2H，abq，J＝9.6Hz)；6.85(1H，dd)；6.99(2H，d)；7.08(1H，m)；7.12(1H，d)；7.30(1H，t)；7.53(2H，d).
5-ethyl-5-(4 '-(methoxyl group-xenyl-4-base oxygen ylmethyl)-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?341(MH+)。
1H?NMR(DMSO-d 6)：δ0.48(3H，t)；1.56-1.74(2H，m)；3.77(3H，s)；3.97，4.11(2H，abq，J＝10.0Hz)；6.94-7.00(4H，m)；7.49-7.54(4H，m)；7.97(1H，s)；10.71(1H，brs)
5-ethyl-5-(4 '-(trifluoromethyl-xenyl-4-base oxygen ylmethyl)-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?378(MH+).
1H?NMR(DMSO-d 6)：δ0.83(3H，t)；1.66(2H，oct)；4.01，4.14(2H，abq，J＝9.8Hz)；7.04(2H，d)；7.67(2H，d)；7.75(2H，d)；7.84(2H，d)；8.01(1H，s)；10.75(1H，bs).
5-ethyl-5-(3 '-(methoxyl group-xenyl-4-base oxygen ylmethyl)-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?340(MH+).
1H?NMR(DMSO-d 6)：δ0.83(3H，t)；1.65(2H，oct)；3.76(3H，s)；3.97，4.10(2H，abq，J＝9.7Hz)；6.93-6.99(3H，m)；7.49-7.53(3H，m)；7.99(1H，s)；10.74(1H，bs).
5-ethyl-5-(4 '-(trifluoromethoxy-xenyl-4-base oxygen ylmethyl)-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?395(MH+).
1H?NMR(DMSO-d 6)：δ0.84(3H，t)；1.56-1.74(2H，m)；4.00，4.13(2H，abq，J＝10.9Hz)；7.01(2H，d)；7.40(2H，d)；7.61，7.72(4H，abq，J＝8.9Hz)；7.79(1H，s)；10.72(1H，bs).
5-ethyl-5-[(4-thiophene phenol-2-base-phenoxymethyl)-and imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?317(MH+)。
1H?NMR(DMSO-d 6)：δ0.82(3H，t)；1.54-1.74(2H，m)；3.97，4.12(2H，abq，J＝10.0Hz)；6.95(2H，d)；7.08(1H，dd)；7.37(1H，dd)；7.44(1H，dd)；7.55(2H，d)；7.98(1H，s)；10.67(1H，s).
5-phenyl-5-(4 '-(trifluoromethyl-xenyl-4-base oxygen ylmethyl)-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?426(MH+).
1H?NMR(DMSO-d 6)：δ4.21，4.62(2H，abq，J＝10.1Hz)；7.10(2H，d)；7.38-7.47(3H，m)；7.61-7.69(4H，m)；7.76，7.84(4H，abq，J＝8.8Hz)；8.76(1H，s)；10.92(1H，bs).
The 5-tertiary butyl-5-(4-pyridin-3-yl-phenoxymethyl)-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?340(MH+)。
1H?NMR(DMSO-d 6)：δ1.02(9H，s)；4.15，4.36(2H，abq，J＝9.9Hz)；7.10(2H，d)；7.70-7.75(3H，m)；8.08(1H，s)；8.39(1H，dd)；8.65(1H，dd)；9.00(1H，s).
The 5-tertiary butyl-5-(4 '-methoxyl group-xenyl-4-base oxygen ylmethyl)-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?368(MH+).
1H?NMR(DMSO-d 6)：δ1.01(9H，s)；3.76(3H，s)；4.10，4.31(2H，abq，J＝9.7Hz)；6.95-7.01(4H，dd)；7.48-7.55(4H，dd)；8.05(1H，s)；10.59(1H，bs).
The 5-tertiary butyl-5-(3 '-trifluoromethyl-xenyl-4-base oxygen ylmethyl)-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?406(MH+).
1H?NMR(DMSO-d 6)：δ1.01(9H，s)；4.14，4.35(2H，abq，J＝9.6Hz)；7.06(2H，d)；7.65-7.69(4H，m)；7.89(1H，s)；7.93(1H，t)；8.08(1H，s)；10.65(1H，s).
The 5-tertiary butyl-5-(4 '-trifluoromethyl-xenyl-4-base salt of wormwood)-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?407(MH+).
1H?NMR(DMSO-d 6)：δ1.03(9H，s)；4.15，4.36(2H，abq，J＝10.0Hz)；7.07，7.68(4H，abq，J＝8.9Hz)；7.76，7.84(4H，abq，J＝8.9Hz)；8.08(1H，s)；10.67(1H，s)。
5-(biphenyl-4-base oxygen ylmethyl)-5-pyridin-4-yl-imidazolidine-2, the 4-diketone
LC-MS(APCI)m/z?360(MH+).
1H?NMR(CD 3OD)：δ4.41，4.71(2H，ABq，J＝9.7Hz)；7.02(2H，d)；7.28(1H，t)；7.39(2H，t)；7.55(2H，d)；8.14(2H，d)；8.81(2H，d).
Embodiment 23
Compound with following general formula
Figure A0281004101891
Synthetic according to the method for describing among the embodiment 21.
Figure A0281004101892
(1): for the NMR data referring to experimental section.
5-[(1,1 '-xenyl-4-base sulphur) methyl]-5-Methylimidazole alkane-2, the 4-diketone
LC-MS(APCI)m/z?313(MH+).
1H?NMR(DMSO-d 6)：δ1.36(3H，s)；3.28(2H，s)；7.34(1H，t)；7.44(4H，t)；7.60(2H，d)；7.64(2H，d)；7.97(1H，s)；10.74(1H，bs).
By being prepared as follows initial substance:
1-(1,1 '-xenyl-4-base sulphur) third-2-ketone
The 1-[(4-bromophenyl) sulphur] third-2-ketone (357mg, 1.46mmol) usefulness phenyl-boron dihydroxide (231mg, 1.89mmol), [1,1 '-two (diphenylphosphine) ferrocene] title complex (36mg) of dichloro palladium (II) and methylene dichloride (1: 1), toluene (20ml), methyl alcohol (7.5ml), saturated sodium carbonate solution (3.5ml) is handled, and stirs 18 hours at 80 ℃.After the cooling, this reaction mixture is also extracted as in the ethyl acetate with the acid treatment of alkene salt.This product (is used 25% ethyl diacetate: the isohexane wash-out), obtain the 277mg product by the flash chromatography purifying on the silicon-dioxide.
GC/MS?m/z：242[M +].
1H?NMR(CDCl 3)：δ2.33(3H，s)；3.73(2H，s)；7.37(1H，s)；7.42-7.48(4H，m)；7.54-7.59(4H，m).
Below mixture according to synthetic 5-[(1,1 '-xenyl-4-base sulphur) methyl]-5-Methylimidazole alkane-2, the description in the 4-diketone prepares.
4 '-{ [(4-methyl-2,5-dioxo alkyl imidazole-4-yl) methyl] sulphur }-1,1 '-xenyl-4-nitrile
Initial substance 4 '-[(2-oxopropyl) sulphur]-1,1 '-xenyl-4-nitrile is according to the description preparation in synthetic 1-(1,1 '-xenyl-4-base sulphur) third-2-ketone.
1H?NMR(DMSO-d 6)：δ1.37(3H，s)；3.30(2H，s)；7.45，7.67(4H，abq，J＝7.5Hz)；7.88(4H，q)；7.99(1H，s)；10.75(1H，bs).
5-methyl-5-[({4 '-[(trifluoromethyl) oxygen base]-1,1 '-xenyl-4-yl } sulphur) methyl] imidazolidine-2,4- Diketone
Initial substance 1-(4 '-[(trifluoromethyl) oxygen base]-1,1 '-xenyl-4-yl } sulphur) third-2-ketone is according to the description preparation in synthetic 1-(1,1 '-xenyl-4-base sulphur) third-2-ketone.
The extremely weak peak 397 (MH+) of LC-MS (APCI) m/z.
1H?NMR(DMSO-d 6)：δ1.33(3H，s)；3.29(2H，s)；7.42-7.45(4H，m)；7.61(2H，d)；7.77(2H，d)；7.99(1H，s)；10.75(1H，s).
Embodiment 24
5-(biphenyl-4-base-hydroxyl-methyl)-5-methyl-imidazolidine-2, the 4-diketone
Figure A0281004101911
With 4-xenyl carboxaldehyde (182mg, 1.0mmol) and the Trimethylamine in water (45%, in water, 160 μ l, 1.0mmol) adding 5-methyl-imidazolidine-2,4-diketone (114mg, 1.0mmol) the warm solution in methyl alcohol (4.0ml) and water (1.0ml).With this reactant at nitrogen as reflux under the inert atmosphere 16 hours.
This solution heating is cooled off, evaporated and stirs in 100/1 mixture of methylene chloride (15ml).Filter, with mixture (10ml) washing precipitate of same solvent, and by the air suction dried, obtain 5-(biphenyl-4-base-hydroxyl-methyl)-imidazolidine-2,4-diketone (190mg), yield 64.1% yield is 60/40 non-enantiomer mixture (according to HNMR).
This isomer mixture (180mg) is dissolved in diox (8ml) and the water (4ml).Go up by preliminary HPLC purifying at Chromasil C18 250/20mm pillar (KR-100-5-C18), during 25 minutes, use acetonitrile/water (0.1% trifluoro hydrochloric acid) (from 20/80 to 40/60 gradient solution wash-out, obtain two kinds of isolating diastereomers, total recovery is 43.5%.
By with HNMR and 5-[(4-chloro-phenyl)-hydroxyl-methyl]]-imidazolidine-2, two kinds of diastereomer contrasts of 4-diketone, each isomer is carried out the initial volumetric structure determination, and wherein two diastereo-isomerism body structures are measured by different NMR experiments in detail preceding.The displacement of 1-NH proton and the phenyl that is connected with imidazolidone is special the sign in this diastereomer is arranged
(RR)-5-(biphenyl-4-base-hydroxyl-(SS)-methyl)-5-methyl-imidazolidine-2, the 4-diketone
1H?NMR(400MHz，DMSO-d 6)：10.19(1H，s)；8.11(1H，s)；7.66(2H，d，J＝7.61Hz)；7.59(2H，d，J＝8.20Hz)；7.45(2H，t，J＝7.68Hz)；7.37(2H，d，J＝8.27Hz)；7.35(1H，t，J＝7.62Hz)；5.92(1H，bs)；4.67(1H，s)；1.44(3H，s).
13C?NMR(400MHz，DMSO-d 6)：176.79；156.25；139.74；139.39；139.14；128.91；128.20；127.37；126.51；125.54；75.32；66.96；21.22.
APCI-MS?m/z：297.3[MH+].
(SR)-5-(biphenyl-4-base-hydroxyl-(RS)-methyl)-5-methyl-imidazolidine-2, the 4-diketone
1H?NMR(400MHz，DMSO-d 6)：10.48(1H，s)；7.67(2H，d，J＝7.48Hz)；7.64(2H，d，J＝8.29Hz)；7.56(1H，s)；7.48-7.45(4H，m)；7.36(1H，t，J＝7.30Hz)；5.75(1H，d，J＝4.73Hz)；4.65(1H，d，J＝3.57Hz)；1.08(3H，s).
13C?NMR(400MHz，DMSO-d 6)：177.89；157.28；139.88；139.44；139.27；128.95；128.47；127.38；126.54；125.89；74.68；66.18；20.22.
APCI-MS?m/z：297.3[MH+].
The compound of describing among the embodiment 25 to 27 prepares with the similar approach that provides among the embodiment 24.
Embodiment 25
(RR)-5-(biphenyl-4-base-hydroxyl-(SS)-methyl)-imidazolidine-2, the 4-diketone
1H?NMR(400MHz，DMSO-d 6)：10.33(1H，s)；8.10(1H，s)；7.66(2H，d，J＝8.20Hz)；7.61(2H，d，J＝8.20Hz)；7.45(2H，dd，J＝8.20/7.20Hz)；7.39(2H，d，J＝8.24Hz)；7.35(1H，t，J＝7.48Hz)；5.89(1H，bs)；4.97(1H，d，J＝2.5Hz)；4.40(1H，d，J＝2.5Hz).
APCI-MS?m/z：283.1[MH+].
(SR)-5-(biphenyl-4-base-hydroxyl-(RS)-methyl)-imidazolidine-2, the 4-diketone
APCI-MS?m/z：283.1[MH+].
Embodiment 26
5-(biphenyl-4-base-hydroxyl-methyl)-thiazolidine-2, the 4-diketone
Figure A0281004101922
(RR)-5-(biphenyl-4-base-hydroxyl-(SS)-methyl)-thiazolidine-2, the 4-diketone
1H?NMR(400MHz，DMSO-d 6)：11.81(1H，s)；7.68(2H，d，J＝8.20Hz)；7.64(2H，d，J＝8.20Hz)；7.46(2H，dd，J＝8.30/7.50Hz)；7.42(2H，d，J＝8.30Hz)；7.36(1H，t，J＝7.50Hz)；6.24(1H，d，J＝3.96Hz)；5.36(1H，t，J＝3.95Hz)；5.06(1H，d，J＝4.03Hz).
APCI-MS m/z:183.1[MH+-thiazolidine-2, the 4-diketone].
(SR)-5-(biphenyl-4-base-hydroxyl-(RS)-methyl)-thiazolidine-2, the 4-diketone
1H?NMR(400MHz，DMSO-d 6)：12.04(1H，s)；7.67(2H，d，J＝8.30Hz)；7.65(2H，d，J＝8.30Hz)；7.51(2H，d，J＝8.20Hz)；7.46(2H，dd，J＝8.20/7.40Hz)；7.36(1H，t，J＝7.40Hz)；6.22(1H，d，J＝5.20Hz)；5.42(1H，dd，J＝5.20/2.60Hz)；5.02(1H，d，J＝2.60Hz).
APCI-MS m/z:183.1[MH+-thiazolidine-2, the 4-diketone].
Embodiment 27
5-(biphenyl-4-base-hydroxyl-methyl)-1-methyl-imidazolidine-2, the 4-diketone
Figure A0281004101931
(RR)-5-(biphenyl-4-base-hydroxyl-(SS)-methyl)-1-methyl-imidazolidine-2, the 4-diketone
1H?NMR(400?MHz，DMSO-d 6)：10.53(1H，s)；7.67(2H，d，J＝7.20Hz)；7.63(2H，d，J＝8.43Hz)；7.46(2H，dd，J＝7.71/7.20Hz)；7.38(2H，d，J＝8.63Hz)；7.35(1H，t，J＝7.63Hz)；6.01(1H，d，J＝4.16Hz)；5.13(1H，dd，J＝4.18/2.60Hz)；4.33(1H，d，J＝2.58Hz)；2.97(3H，s).
13C?NMR(400MHz，DMSO-d 6)：176.63；156.83；139.78；138.97；138.95；128.89；127.35；127.13；126.53；125.91；71.28；67.81；28.63.
APCI-MS?m/z：297.1[MH+]
(SR)-5-(biphenyl-4-base-hydroxyl-(RS)-methyl)-1-methyl-imidazolidine-2, the 4-diketone
1H?NMR(400MHz，DMSO-d 6)：10.73(1H，s)；7.70(4H，m)；7.54(2H，d，J＝8.22Hz)；7.46(2H，dd，J＝8.20/7.10Hz)；7.36(1H，t，J＝7.11Hz)；5.96(1H，d，J＝6.06Hz)；5.11(1H，dd，J＝6.06/2.14Hz)；4.38(1H，d，J＝2.14Hz)；2.33(3H，s).
APCI-MS?m/z：297.1[MH+]
Embodiment 28
5-[hydroxyl-(3-phenoxy group-phenyl)-methyl]-imidazolidine-2, the 4-diketone
Figure A0281004101941
This compound is according to the method preparation that provides among the embodiment 24, but by THPLC, flash chromatography (SiO, methylene chloride: gradient to 100/4) preparation obtains 60 title compounds, is white solid, yield 20.1% (non-enantiomer mixture).HNMR confirms that the ratio of the mixture of this diastereomer is 1: 1.
1H?NMR(400MHz，DMSO-d 6)：10.51(1H，bs)；10.37(1H，bs)；8.04(1H，s)；7.56(1H，s)；7.40-7.29(6H，m)；7.1?6-7.09(4H，m)；7.05-7.02(4H，m)；6.96(2H，d，J＝8.71Hz)；6.89(2H，m)；5.89(1H，d，J＝3.91Hz)；5.78(1H，d，J＝5.68Hz)；4.93-4.90(2H，m)；4.34(1H，dd)；4.25(1H，dd).
13C?NMR(400MHz，DMSO-d 6)：174.04；173.05；158.09；157.40；156.89；156.83；156.31；155.63；144.01；141.69；129.96；129.94；129.55；129.15；123.20；123.06；122.26；121.28；118.44；118.06；118.02；117.80；117.46；116.76；71.98；70.28；64.01.
APCI-MS?m/z：281.1[MH+-H2O].
Embodiment 29
5-[hydroxyl-(4-phenoxy group-phenyl)-methyl]-imidazolidine-2, the 4-diketone
Figure A0281004101942
This mixture is according to the method preparation that provides among the embodiment 24, but by HPLC, flash chromatography (SiO, methylene chloride: gradient to 100/3) preparation obtains the 40mg title compound, is white solid, yield 13.4% (non-enantiomer mixture).HNMR confirms that the ratio of the mixture of this diastereomer is 1: 1.
1H?NMR(400MHz，DMSO-d 6)：10.49(1H，bs)；10.36(1H，bs)；8.04(1H，s)；7.55(1H，s)；7.41-7.35(6H，m)；7.31(2H，d，J＝8.60Hz)；7.13(2H，ddd，J＝7.44/3.52/1.14Hz)；7.01-6.92(8H，m)；5.84(1H，d，J＝3.76Hz)；5.74(1H，d，J＝5.55Hz)；4.91(2H，m)；4.34(1H，dd，J＝3.03/1.05Hz)；4.22(1H，DD，2.68/1.52Hz).
APCI-MS?m/z：281.1[MH+-H2O].
Embodiment 30
Be prepared as follows compound according to the method for describing among the top embodiment.
5-[(4 '-fluoro-xenyl-4-yl)-hydroxyl-methyl]-imidazolidine-2, the 4-diketone
APCI-MS?m/z：283[MH+-H2O].
5-[(4 '-fluoro-xenyl-4-yl)-hydroxyl-methyl]-5-methyl-imidazolidine-2, the 4-diketone
APCI-MS?m/z：314.9[MH+].
5-[(4 '-fluoro-xenyl-4-yl)-hydroxyl-methyl]-5-isobutyl--imidazolidine-2, the 4-diketone
Figure A0281004101961
APCI-MS?m/z：357.1[MH+].
5-[(4 '-chloro-xenyl-4-yl)-hydroxyl-methyl]-imidazolidine-2, the 4-diketone
APCI-MS?m/z：298.9[MH+-H2O].
5-[(4 '-chloro-xenyl-4-yl)-hydroxyl-methyl]-5-methyl-imidazolidine-2, the 4-diketone
APCI-MS?m/z：331[MH+].
5-[(4 '-chloro-xenyl-4-yl)-hydroxyl-methyl]-5-isobutyl--imidazolidine-2, the 4-diketone
Figure A0281004101971
APCI-MS?m/z：373.1[MH+].
5-(biphenyl-4-yl)-hydroxyl-methyl]-5-methylol-imidazolidine-2, the 4-diketone
Figure A0281004101972
APCI-MS?m/z：313.O[MH+].
Embodiment 31
These compounds provide in describing the compound of above-mentioned general formula III according to path 4) in method C synthetic.
(a) preparation glycolylurea intermediate (the method A in the path 4)
According to following path 5, glycolylurea 5 prepares A by amino acid 3 and isolating intermediate 4 in two steps.
Path 5 (method A)
Figure A0281004101973
Table 2 is listed synthetic intermediate glycolylurea.The general method of preparation is as follows.(5.1g, 63mmol) slurry in water (75ml) is 80 ℃ of about 1 hour of heating down with amino acid 3 (25mmol) and potassium cyanate.This clear solution is cooled to 0 ℃ also is acidified to about pH with concentrated hydrochloric acid (aqueous solution).Gained white depositions 4 was heated 0.5-1 hour under refluxing, then in cooled on ice.Can not reach fully after 1 hour in heating in some cases and transform.In these cases, under the same approach situation with thick mass treatment.White solid is filtered, wash with water, dry and by HNMR lcms analysis.
Table 2: intermediate glycolylurea
Title: Yield (%) ??APCI-MS ?m/z：[MH +]
5-(4-chloro-benzyl)-imidazolidine-2, the 4-diketone ??87 ????224.9
[3-(2,5-dioxo-imidazolidine-4-yl)-propyl group] carboxylamine benzyl ester ??50 ????292.0
5-isobutyl--imidazolidine-2, the 4-diketone ??85 ????157.0
5-benzyl sulfenyl (sulfanyl) methyl-imidazolidine-2, the 4-diketone ??87 ????237.0
5-methyl sulfenyl (sulfanyl) methyl-imidazolidine-2, the 4-diketone ??45 ????161.0
5-cyclohexyl sulfenyl (sulfanyl) methyl-imidazolidine-2, the 4-diketone ??63 ????197.1
5-sec-butyl imidazolidine-2, the 4-diketone ??52 ????157.0
5-styroyl imidazolidine-2, the 4-diketone ??94 ????205.1
5-butyl imidazole alkane-2, the 4-diketone ??82 ????157.0
5-isopropylimdazole alkane-2, the 4-diketone ??49
5-(1H5-indol-3-yl methyl) imidazolidine-2, the 4-diketone ??94 ????230.0
5-(2-hydroxyethyl)-imidazolidine-2, the 4-diketone ??36
(b) Prepare intermediate aldehydes (the method B in the path 4)
The substituted benzaldehyde by the Suzuki coupling between different commercial phenyl oxide compounds and 4-formyl radical phenyl-boron dihydroxide preparation wherein is according to following path 6.
Path 6 (method B)
Figure A0281004101981
4-pyridine-2-base-phenyl aldehyde
Compound is according to being prepared as follows.(195mg, 1.3mmol), (102.7mg is 0.65mmol) with powder K for the 2-bromopyridine with A mixture of 4-formyl radical phenyl-boron dihydroxide 2CO 3(1.07g, 7.8mmol) the mixture deoxidation (vacuum and argon gas) in Zai diox (12ml) and the water (2ml).(30mg 0.2mol%) and with this mixture stirred 2 hours down at 80 ℃ under argon gas to add palladium diacetate.
This slurry is cooled to room temperature.Precipitation is also filtered, and obtains thick product.Preliminary HPLC (Chromasil C18 pillar, acetonitrile, water and trifluoroacetic acid) obtains title compound 4-pyridine-2-base-phenyl aldehyde (72mg, in 60% yield.
1H?NMR(400MHz，DMSO-d 6)：δ10.07(1H，s)；8.73(1H，d，J＝4.20Hz)；8.31(2H，d，J＝8.20)；8.11(1H，d，J＝8.01)；8.03(2H，d，J＝8.20)；7.97(1H，m).
APCI-MS?m/z：184.2[MH+].
Other phenyl aldehyde (providing in table 3) is according to identical method production.
Table 3: substituted benzaldehyde
Title: Yield (%) ??APCI-MS?m/z：
4 '-formyl radical-xenyl-4-nitrile ????65 ????208.0
4 '-formyl radical-xenyl-3-nitrile ????208.0
4 '-methoxyl group-xenyl-4-aldehyde (carbaldehyde) ????50 ????213.1
3-methoxyl group-xenyl-4-aldehyde (carbaldehyde) ????62 ????213.1
Biphenyl-4,4 '-di aldehyde (carbaldehyde) ????211.0
Acetate 4 ' formyl radical-xenyl-3-base ester ????239.1
The basic ester of acetate 4 ' formyl radical-xenyl-4 ????239.1
N-(4 '-formyl radical-xenyl-3-yl)-ethanamide ????75 ????240.1
4 '-methylol-xenyl-4-aldehyde (carbaldehyde) ????55 ????213.1
3 '-fluoro-xenyl-4-aldehyde (carbaldehyde) ????70 ????201.1
4-pyridin-3-yl-phenyl aldehyde ????67 ????184.2
3 ', 4 '--two fluoro-xenyl-4-aldehyde (carbaldehyde) ????72 ????219.1
4-pyridin-4-yl-phenyl aldehyde ????67 ????184.2
N-[4-(4-formyl radical-phenyl)-pyridine-2-yl]-ethanamide ????30 ????241.0
4-benzo [1,3] dioxolane-5-base-phenyl aldehyde ????20 ????226.1
(c) The aldol condensation of intermediate glycolylurea and aldehyde (the method C in the path 4)
General technology is by synthetic 5-{[4-(4-fluoro-phenoxy group)-phenyl]-methyl-methyl }-5-propyl group-imidazolidine-2,4-diketone example
5-{[4-(4-fluoro-phenoxy group)-phenyl]-methyl-methyl }-5-propyl group-imidazolidine-2, the 4-diketone
With commercial 4-(4-fluoro-phenoxy group)-phenyl aldehyde (201.5mg, 1.0mmol), 5-propyl group-glycolylurea (438mg, 3.08mmol) and the aqueous solution of 45% Trimethylamine 99 (0.240ml, 1.5mmol) backflow 20 hours in ethanol (12ml) and water (3ml).
Evaporation and preliminary HPLC (C18 pillar, acetonitrile, water and trifluoroacetic acid), title compound 5-{[4-(4-fluoro-phenoxy group)-phenyl is provided]-methyl-methyl }-5-propyl group-imidazolidine-2, and the 4-diketone (11mg, 0.03mmol), 3% yield is the white solid form of pure racemic modification.
1HNMR(300MHz，DMSO-d 6)：δ10.71(1H，s)；7.99(1H，s)；7.70(2H，dd，J＝4.38，5.37Hz)；7.75(2H，d，J＝8.44Hz)；7.35(2H，d，J＝8.03Hz)；7.27(2H，dd，J＝4.59，8.60Hz)；5.89(1H，d，J＝4.42Hz)；4.66(1H，d，J＝4.34Hz)；1.96(1H，dd，J＝12.89，4.36Hz)；1.71(1H，dd；J＝12.95，4.77Hz)；1.32(1H，m)；1.10(1H，m)；0.89(3H，t，J＝7.49Hz).
APCI-MS?m/z：343.1[MH +-OH].
Following compound is according to identical method preparation.
5-[4-phenoxy group-phenyl]-hydroxyl-methyl]-5-methyl-imidazolidine-2, the 4-diketone
Figure A0281004102002
1H?NMR(400MHz，DMSO-d 6)：δ10.12(1H，bs)；8.06(1H，s)；7.38(2H，dd，J＝3.94，7.60Hz)；7.28(2H，d，J＝8.62Hz)；7.13(1H，t，J＝7.43Hz)；6.96(2H，d，J＝8.75Hz)；6.91(2H，d，J＝8.61Hz)；5.89(1H，d，J＝4.33?Hz)；4.62(1H，d，J＝4.48Hz)；1.41(3H，s).
APCI-MS?m/z：313.0[MH +].
4-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-piperidines-1-carboxylic acid benzyl ester
By commercial initial substance preparation.
APCI-MS?m/z：362.1[MH +].
5-[(4 '-fluoro-xenyl-4-yl)-hydroxyl-methyl]-imidazolidine-2, the 4-diketone
By commercial initial substance preparation.
Figure A0281004102012
1HNMR(400MHz，DMSO-d 6)：δ10.32(1H，s)；8.09(1H，s)；7.71(2H，dd，J＝4.47，5.60Hz)；7.60(2H，d，J＝8.27Hz)；7.38(2H，d，J＝8.33Hz)；7.28(2H，dd，J＝5.05，8.68Hz)；5.88(1H，d，J＝3.90Hz)；4.97(1H，t，J＝3.29Hz)；4.39(1H，d，J＝2.64Hz).
APCI-MS?m/z：301.2[MH +].
5-ethyl-5-[(4 '-fluoro-xenyl-4-yl)-hydroxyl-methyl]-imidazolidine-2, the 4-diketone
By 4 '-fluoro-xenyl-4-aldehyde (carbaldehyde) and 5-ethyl-imidazoles ide-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102021
1H?NMR(400MHz，DMSO-d 6)：δ10.18(1H，s)；7.96(1H，s)；7.69(2H，dd，J＝8.77/5.53Hz)；7.57(2H，d，J＝8.20Hz)；7.35(2H，d，J＝8.20Hz)；7.26(2H，t，J＝8.87Hz)；5.87(1H，d，J＝4.39Hz)；4.66(1H，d，4.39Hz)；1.98(1H，m)；1.75(1H，m)；0.78(3H，t，J＝7.34Hz).
APCI-MS?m/z：329.1[MH +]
5-[(4 '-fluoro-xenyl-4-yl)-hydroxyl-methyl]-5-propyl group-imidazolidine-2, the 4-diketone
By 4 '-fluoro-xenyl-4-aldehyde (carbaldehyde) and 5-propyl group-imidazolidine-2, the 4-diketone carries out aldol condensation production.
1H?NMR(400MHz，DMSO-d 6)：δ10.16(1H，s)；7.98(1H，s)；7.69(2H，dd，J＝8.68/5.44Hz)；7.56(2H，d，J＝8.20Hz)；7.34(2H，d，J＝8.20Hz)；7.26(2H，t，J＝8.77Hz)；5.87(1H，d，J＝4.39Hz)；4.64(1H，d，4.39Hz)；1.94(1H，m)；1.70(1H，m)；1.31(1H，m)；1.10(1H，m)；0.88(3H，t，J＝7.34Hz).
APCI-MS?m/z：343.1[MH +]
The 5-[hydroxyl-(4 '-methoxyl group-xenyl-4-yl)-methyl]-5-methyl-imidazolidine-2, the 4-diketone
By 4 '-methoxyl group-xenyl-4-aldehyde (carbaldehyde) and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102023
1H?NMR(400MHz，DMSO-d 6)：δ10.16(1H，s)；8.08(1H，s)；7.59(2H，d，J＝8.77Hz)；7.52(2H，d，J＝8.20Hz)；7.31(2H，d，J＝8.20Hz)；6.99(2H，d，J＝8.58Hz)；5.87(IH，d，J＝4.39Hz)；4.63(1H，d，4.39Hz)；3.77(3H，t)；1.42(3H，s).
APCI-MS?m/z：327.1[MH +]
The 5-[hydroxyl-(3 '-methoxyl group-xenyl-4-yl)-methyl]-5-methyl-imidazolidine-2, the 4-diketone
By 3-methoxyl group-xenyl-4-aldehyde (carbaldehyde) and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102031
1H?NMR(400MHz，DMSO-d 6)：δ10.18(1H，s)；8.08(1H，s)；7.59(2H，d，J＝8.01Hz)；7.35(3H，m)；7.21(1H，d，J＝7.63Hz)；7.17(1H，s)；6.91(1H，dd，J＝8.11/2.19)；5.91(1H，d，J＝4.39Hz)；4.65(1H，d，4.39Hz)；3.81(3H，t)；1.43(3H，s).
APCI-MS?m/z：327.1[MH +]
4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-4-nitrile
By 4 '-formyl radical-xenyl-4-nitrile and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
1H?NMR(400?MHz，DMSO-d 6)：δ10.18(1H，s)；8.11(1H，s)；7.89(4H，m)；7.69(2H，d，J＝8.20)；7.40(2H，d，J＝8.20Hz)；5.97(1H，d，J＝4.39Hz)；4.67(1H，d，4.39Hz)；3.81(3H，t)；1.43(3H，s).
APCI-MS?m/z：322.1[MH +]
4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-3-nitrile
By 4 '-formyl radical-xenyl-3-nitrile and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
1H?NMR(400MHz，DMSO-d 6)：δ10.18(1H，s)；8.14(1H，s)；8.11(1H，s)；8.02(1H，d，J＝8.01Hz)；7.80(1H，d，J＝7.63Hz)；7.69(2H，d，J＝8.20Hz)；7.64(1H，t，J＝7.82Hz)；7.38(2H，d，J＝8.20Hz)；5.96(1H，d，J＝4.20Hz)；4.67(1H，d，3.81Hz)；1.42(3H，s).
APCI-MS?m/z：322.1[MH +]
4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-4-aldehyde (carbaldehyde)
By biphenyl-4-4 '-dialdehyde (carbaldehyde) and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102042
1H?NMR(400MHz，DMSO-d 6)：δ10.19(1H，s)；10.03(1H，s)；8.12(1H，s)；7.97(2H，d，J＝8.40Hz)；7.91(2H，d，J＝8.40)；7.71(2H，d，J＝8.20Hz)；7.40(2H，d，J＝8.40Hz)；5.97(1H，d，J＝4.39Hz)；4.67(1H，d，4.39Hz)；3.81(3H，t)；1.43(3H，s).
APCI-MS?m/z：325.1[MH +].
Acetate 4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-3-base ester by acetate 4 '-formyl radical-xenyl-3-base ester and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102043
1H?NMR(400MHz，DMSO-d 6)：δ10.18(1H，s)；8.16(1H，s)；8.11(1H，s)；7.92(1H，dd，J＝7.72/1.24Hz)；7.66(2H，d，J＝8.40)；7.60(1H，t，J＝7.73Hz)；7.38(2H，d，J＝8.40Hz)；5.94(1H，d，J＝4.39Hz)；4.67(1H，d，4.39Hz)；2.63(3H，s)；1.42(3H，s).
APCI-MS?m/z：321.1[MH +-H 2O].
Acetate 4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-4-base-ester
By the basic ester of acetate 4 ' formyl radical-xenyl-4 and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102051
1H?NMR(400MHz，DMSO-d 6)：δ10.19(1H，s)；8.11(1H，s)；8.01(2H，d，J＝8.39Hz)；7.82(2H，d，J＝8.20)；7.68(2H，d，J＝8.20Hz)；7.39(2H，d，J＝8.20Hz)；5.96(1H，d，J＝4.39Hz)；4.67(1H，d，4.39Hz)；2.59(3H，t)；1.43(3H，s).
APCI-MS?m/z：321.1[MH +-H 2O].
N-{4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-3-yl }-ethanamide
By N-(4 '-formyl radical-xenyl-3-yl)-ethanamide and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
1H?NMR(400MHz，DMSO-d 6)：δ10.17(1H，s)；9.98(1H，s)；8.08(1H，s)；7.87(1H，s)；7.50(3H，m)；7.32(4H，m)；5.91(1H，d，J＝4.56Hz)；4.64(1H，d，4.28Hz)；2.05(3H，s)；1.42(3H，s).
APCI-MS?m/z：354.1[MH +].
5-[hydroxyl-(4-methylol-xenyl-4-yl)-methyl]-5-methyl-imidazolidine-2, the 4-diketone
By 4 '-methylol-xenyl-4-aldehyde (carbaldehyde) and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102061
1H?NMR(400MHz，DMSO-d 6)：δ10.17(1H，s)；8.09(1H，s)；7.61(2H，d，J＝8.20Hz)；7.57(2H，d，J＝8.20)；7.38(2H，d，J＝8.20Hz)；7.34(2H，d，J＝8.20Hz)；5.90(1H，d，J＝4.39Hz)；5.19(1H，T，J＝5.72Hz)；4.65(1H，d，4.39Hz)；4.52(2H，d，J＝5.72Hz)；1.43(3H，s).
APCI-MS?m/z：327.1[MH +].
5-[(4-benzyloxy-phenyl)-hydroxyl-methyl]-5-methyl-imidazolidine-2, the 4-diketone
By 4-benzyloxy-phenyl aldehyde and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
1H?NMR(400MHz，DMSO-d 6)：δ10.10(1H，s)；8.01(1H，s)；7.46-7.27(5H，m)；7.18(2H，d，J＝8.58Hz)；6.89(2H，d，J＝8.58Hz)；5.75(1H，d，J＝4.39Hz)；5.04(2H，s)；4.55(1H，d，J＝4.39Hz)；1.43(3H，s).
APCI-MS?m/z：309.1[MH +-H 2O].
5-[hydroxyl-(4 pyridin-3-yls-phenyl)-methyl]-5-methyl-imidazolidine-2, the 4-diketone
By 4-pyridin-3-yl-phenyl aldehyde and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102063
APCI-MS?m/z：298.1[MH +]
5-[(3 '-fluoro-xenyl-4-yl)-hydroxyl-methyl]-5-methyl-imidazolidine-2, the 4-diketone by 3 '-fluoro-xenyl-4-aldehyde (carbaldehyde) and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
1H?NMR(400MHz，DMSO-d 6)：δ10.17(1H，s)；8.10(1H，s)；7.63(1H，d，J＝8.20Hz)；7.49(3H，m)；7.36(2H，d，J＝8.20Hz)；7.17(1H，m)；5.93(1H，d，J＝4.20Hz)；4.66(1H，d，3.81Hz)；1.42(3H，s).
APCI-MS?m/z：315[MH +].
5-[hydroxyl-(4-phenyl vinyl-phenyl)-methyl]-5-methyl-imidazolidine-2, the 4-diketone
(J Org Chem 1998,63 (23) 8551-8553) synthesizes initial aldehyde according to Thorand S.et.al.
Figure A0281004102072
1H?NMR(400MHz，DMSO-d 6)：δ10.18(1H，s)；8.08(1H，s)；7.53(2H，m)；7.45(2H，d，J＝8.40Hz)；7.41(3H，m)；7.30(2H，d，J＝8.20Hz)；5.99(1H，d，J＝4.58Hz)；4.64(1H，d，4.39Hz)；1.41(3H，s).
APCI-MS?m/z：321.1[MH +]
5-[hydroxyl-(4 pyridin-4-yls-phenyl)-methyl]-5-methyl-imidazolidine-2, the 4-diketone
By 4-pyridin-4-yl-phenyl aldehyde and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
1H?NMR(400MHz，DMSO-d 6)：δ10.19(1H，s)；8.61(2H，m)；8.12(1H，s)；7.74(2H，d，J＝8.39)；7.70(2H，m)；7.41(2H，d，J＝8.20Hz)；5.99(1H，s，)；4.67(1H，s)；1.42(3H，s).
APCI-MS?m/z：298.1[MH +].
N-{4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-4-yl }-ethanamide
By N-(4 ' formyl radical-xenyl-4-yl)-ethanamide and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102081
APCI-MS?m/z：354.1[MH +]
N-(5-{4-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-phenyl }-pyridine-2-yl)-ethanamide
By N-[4-(4-formyl radical-phenyl)-pyridine-2-yl]-ethanamide and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102082
APCI-MS?m/z：355.1[MH +]
5-[(3 ', 4 '-two fluoro-xenyl-4-yls)-hydroxyl-methyl]-5-methyl-imidazolidine-2, the 4-diketone
By 3 ', 4 '-two fluoro-xenyls-4-aldehyde (carbaldehyde) and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
1H?NMR(400MHz，DMSO-d 6)：δ10.16(1H，s)；8.10(1H，s)；7.75(1H，m)；7.61(2H，d，J＝8.27Hz)；7.50(2H，m)；7.35(2H，d，J＝8.27)；5.93(1H，d，J＝3.99Hz)；4.66(1H，d，3.98Hz)；1.41(3H，s).
APCI-MS?m/z：333[MH +].
The 5-[hydroxyl-(4-[1,2,3] thiadiazoles-5-base-phenyl)-methyl]-5-methyl-imidazolidine-2, the 4-diketone
By 4-[1,2,3] thiadiazoles-5-base-phenyl aldehyde and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
APCI-MS?m/z：305[MH +]
5-{[5-(2-chloro-4-trifluoromethyl-phenyl)-furans-2-yl]-hydroxyl-methyl }-5-methyl-imidazolidine-2, the 4-diketone
By 5-(3-chloro-4-trifluoromethyl-phenyl)-furans-2-aldehyde (carbaldehyde) and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
APCI-MS?m/z：389[MH +]
5-{[5-(4-chloro-phenyl sulfenyl)-thiophene phenol-2-yl]-hydroxyl-methyl }-5-methyl-imidazolidine-2, the 4-diketone
By 5-(4-chloro-phenyl sulfenyl)-thiophene phenol-2-aldehyde (carbaldehyde) and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102093
APCI-MS?m/z：350.9[MH +-H 2O]
5-{[4-(the 4-tertiary butyl-thiazol-2-yl)-phenyl]-hydroxyl-methyl }-5-methyl-imidazolidine-2, the 4-diketone
By 4-(the 4-tertiary butyl-thiazole 2-yl)-phenyl aldehyde and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
APCI-MS?m/z：360[MH +]
5-{[4-(2-chloro-6-fluoro-benzyloxy)-3-methoxyl group-phenyl]-hydroxyl-methyl }-5-methyl-imidazolidine-2, the 4-diketone
By 4-(2-chloro-6-fluoro-benzyloxy)-3-methoxyl group-bemnzaldehyde and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102102
APCI-MS?m/z：391[MH +-H 2O]
5-{[2-(4-chloro-phenyl sulfenyl)-phenyl]-hydroxyl-methyl }-5-methyl-imidazolidine-2, the 4-diketone
By 2-(4-chloro-phenyl sulfenyl)-phenyl aldehyde and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102103
5-{[1-(4-chloro-phenyl H-pyrroles-2-yl)-hydroxyl-methyl]-5-methyl-imidazolidine-2, the 4-diketone
(4-chloro-phenyl-1H-pyrroles-2-aldehyde (carbaldehyde) and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production by 1-.
Figure A0281004102111
APCI-MS?m/z：302.1[MH +-H 2O]
5-[hydroxyl-(2-pyridine-2-base-thiophene phenol-2-yl)-methyl]-5-methyl-imidazolidine-2, the 4-diketone
By 5-pyridine-2-base-thiophene phenol-2-aldehyde (carbaldehyde) and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
APCI-MS?m/z：304[MH +]
5-[hydroxyl-(5-thiophene phenol-2-H-pyrazole-3-yl)-methyl]-5-methyl-imidazolidine-2, the 4-diketone
By 5-thiophene phenol-2-base-2H-pyrazoles-3-aldehyde (carbaldehyde) and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102113
APCI-MS?m/z：293.1[MH +]
5-{ hydroxyl-[5-(4-trifluoromethyl-phenyl H-pyrazole-3-yl)-5-methyl-imidazolidine-2,4-diketone
(4-trifluoromethyl-phenyl-2H-pyrazoles-3-aldehyde (carbaldehyde) and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production by 5-.
Figure A0281004102114
APCI-MS?m/z：355[MH +]
5-(biphenyl-4-base-hydroxyl-methyl)-5-(4-chloro-benzyl)-imidazolidine-2, the 4-diketone
By biphenyl-4-aldehyde (carbaldehyde) and 5-(4-chloro-benzyl)-imidazolidine-2, the 4-diketone carries out aldol condensation production.
1H?NMR(400MHz，DMSO-d 6)：δ9.89(1H，s)；8.29(1H，s)；7.65(2H，d，J＝7.73Hz)；7.59(2H，d，J＝8.20Hz)；7.43(2H，m)；7.39(2H，d，J＝8.20Hz)；7.32(3H，m)；7.20(2H，d，J＝8.39Hz)；6.13(1H，d，J＝4.01Hz)；4.85(1H，d，4.01Hz)；3.28(1H，d，J＝13.35Hz)；3.04(1H，d，J＝13.35).
APCI-MS?m/z：407.2[MH +]
5-dibenzylsulfide ylmethyl-5-(biphenyl-4-base-hydroxyl-methyl)-imidazolidine-2, the 4-diketone
By biphenyl-4-aldehyde (carbaldehyde) and 5-dibenzylsulfide ylmethyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
APCI-MS?m/z：419.2[MH +]
5-(biphenyl-4-base-hydroxyl-methyl)-5-methyl sulfenyl methyl-imidazolidine-2, the 4-diketone
By biphenyl-4-aldehyde (carbaldehyde) and 5-methyl sulfenyl methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102131
APCI-MS?m/z：343.1[MH +]
5-(biphenyl-4-base-hydroxyl-methyl)-5-cyclohexyl methyl-imidazolidine-2, the 4-diketone
By biphenyl-4-aldehyde (carbaldehyde) and 5-cyclohexyl methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
APCI-MS?m/z：379.3[MH +]
5-(biphenyl-4-base-hydroxyl-methyl)-5-styroyl-imidazolidine-2, the 4-diketone
By biphenyl-4-aldehyde (carbaldehyde) and 5-styroyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102133
APCI-MS?m/z：387.3[MH +]
5-(biphenyl-4-base-hydroxyl-methyl)-5-(2-hydroxyl-ethyl)-imidazolidine-2, the 4-diketone
By biphenyl-4-aldehyde (carbaldehyde) and 5-(2-hydroxyl-ethyl)-imidazolidine-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102141
APCI-MS?m/z：309.2[MH +-H 2O]
The 5-[hydroxyl-(4 '-methoxyl group-xenyl-4-yl)-methyl]-imidazolidine-2, the 4-diketone
By 4 '-methoxyl group-xenyl-4-aldehyde (carbaldehyde) and imidazolidine-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102142
1H?NMR(400MHz，DMSO-d 6)：δ10.30(1H，s)；8.06(1H，s)；7.60(2H，d，J＝8.77Hz)；7.54(2H，d，J＝8.39Hz)；7.33(2H，d，J＝8.20Hz)；7.00(2H，d，J＝8.77Hz)；5.83(1H，d，J＝3.81Hz)；4.94(1H，t，J＝3.34)；4.33(1H，d，J＝2.67Hz)；3.77(3H，s).
APCI-MS?m/z：295[MH +-H 2O]
5-(biphenyl-4-base-hydroxyl-methyl)-5-pyridin-4-yl methyl-imidazolidine-2, the 4-diketone
By biphenyl-4-aldehyde (carbaldehyde) and 5-pyridin-4-yl methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102143
APCI-MS?m/z：374.2[MH +]
5-(hydroxyl-3-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-phenyl } methyl)-5-methyl-imidazolidine-2, the 4-diketone
By 4-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-phenyl aldehyde and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
APCI-MS?m/z：450.2[MH +]
5-[(4-{2-[4-(3-chloro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-oxyethyl group }-phenyl)-hydroxyl-methyl]]-5-methyl-imidazolidine-2, the 4-diketone
By commercial initial substance preparation.
Figure A0281004102152
APCI-MS?m/z：528.3[MH +].
Embodiment 32
These compounds are according to the method D (Suzuki coupling) in (providing in the top description .) synoptic diagram 4, by commercial aryl boric acid and 5-[hydroxyl-(4-iodo-phenyl)-methyl]-5-methyl-imidazolidine-2,4-diketone or following 5-[hydroxyl-(4-iodo-phenyl)-methyl]-imidazolidine-2, the 4-diketone is produced.
5-[hydroxyl-(4-iodo-phenyl)-methyl]-5-methyl-imidazolidine-2, the 4-diketone
With 4-iodo-phenyl aldehyde (9.280g, 40.0mmol), 5-methyl-glycolylurea (4.564g, 40.0mmol) and the 45% Trimethylamine aqueous solution (6.40ml, 40.0mmol) in ethanol (60ml) and water (40ml) under nitrogen atmosphere the backflow 20 novels.Form white precipitate.After at room temperature cooling off about 15 minutes, filter the collecting precipitation thing, (50%, 50ml), water (50ml) and ether (50ml) order are washed with ethanol.By air suction filtration drying, obtain title compound 5-[hydroxyl 1-(4-iodo-phenyl)-methyl]-imidazolidine-2, (7.968g, 23.0mol), yield 57.5% is the white solid of pure racemic modification form to the 4-diketone.
1HNMR(300MHz，DMSO-d 6)：δ10.19(1H，s)；8.08(1H，s)；7.64(2H，d，J＝8.55Hz)；7.07(2H，d，J＝8.43Hz)；5.98(1H，d，J＝4.49Hz)；4.57(1H，d，J＝4.32Hz)；1.40(3H，s).
APCI-MS?m/z：346.9[MH +].
5-[hydroxyl-(4-iodo-phenyl)-methyl]-imidazolidine-2, the 4-diketone
According to above-mentioned preparation 5-[hydroxyl-(4-iodo-phenyl)-methyl]-5-methyl-imidazolidine-2, the mode that the 4-diketone is identical prepares.
1HNMR(300MHz，DMSO-d 6)：δ10.32(1H，s)；8.06(1H，s)；7.66(2H，d，J＝8.14Hz)；7.10(2H，d，J＝8.27Hz)；5.91(1H，d，J＝3.90Hz)；4.87(1H，t，J＝2.70Hz)；4.34(1H，d，J＝2.48Hz).
APCI-MS?m/z：333.1[MH +].
4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-4-carboxylic acid
Figure A0281004102161
With 4-carboxyl-phenyl-boric acid (214mg, 1.3mmol), 5-[hydroxyl-(4-iodo-phenyl)-methyl]-imidazolidine-2,4-diketone (347mg, 1.0mmol) and sodium bicarbonate (318mg, 3.8mmol) stirring the mixture by vacuum nitrogen deoxidation 3 times in acetone (5.0ml) and water (5.0ml).Add palladium diacetate (20mg, yyy mmol) and repeat deoxidation, then this mixture is stirred 90 at 50 ℃ under nitrogen atmosphere.
Allow solid precipitation, supernatant liquid is distributed in water (20ml), between ethyl diacetate (15ml) and the ether (15ml).(extraction of ethyl diacetate (15ml) and ether (15ml) is used in aq, 10ml) acidifying then with 1M HCl with water.The evaporation organic phase obtains the thick product of 340mg, will also filter with trifluoroacetic acid (100microl) recrystallization in its Zai diox (6ml) and the water (6ml).Preliminary HPLC (post, acetonitrile/water/trifluoroacetic acid), obtain title compound 4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-(114mg 0.33mmol), is white solid, yield 33.5% to xenyl-4-carboxylic acid.
1H?NMR(400MHz，DMSO-d 6)：δ10.20(1H，s)；8.13(1H，s)；8.00(2H，d，J＝8.33Hz)；7.79(2H，d，J＝8.49Hz)；7.67(2H，d，J＝8.39Hz)；7.40(2H，d，J＝8.48Hz)；5.97(1H，bs)；4.68(1H，s)；1.44(3H，s).
APCI-MS?m/z：341[MH +].
Below compound according to above-mentionedly be used to prepare 4 '-mode that [hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-the 4-carboxylic acid is identical prepares.
The 5-[hydroxyl-(4 '-methyl sulfenyl-xenyl-4-yl)-methyl]-5-methyl-imidazolidine-2, the 4-diketone
Figure A0281004102171
1H?NMR(300MHz，DMSO-d 6)：δ10.18(1H，s)；8.10(1H，s)；7.62(2H，d，J＝8.61Hz)；7.57(2H，d，J＝8.42Hz)；7.35(2H，d，J＝5.73?Hz)；7.32(2H，d，J＝6.30Hz)；
5.91(1H，d，J＝4.32Hz)；4.65(1H，d，J＝4.31Hz)；2.50(3H，s)；1.43(3H，s).
APCI-MS?m/z：343.0[MH +].
5-[hydroxyl-(4-naphthalene-2-base phenyl)-methyl]-5-methyl-imidazolidine-2, the 4-diketone
APCI-MS?m/z：347.1[MH +]
The 5-[hydroxyl-[1,1 '; 4,1 "] terpenyl-4 "-Ji-methyl)-5-methyl-imidazolidine-2, the 4-diketone
Figure A0281004102181
APCI-MS?m/z：373.1[MH +]
5-[(3 '-benzyloxy-xenyl-4-yl)-hydroxyl-methyl]-5-methyl-imidazolidine-2, the 4-diketone
APCI-MS?m/z：403.1[MH +].
5-[(4-benzo [1,3] dioxole (dioxol)-5-base-phenyl)-hydroxyl-methyl]-imidazolidine-2, the 4-diketone
Figure A0281004102183
1H?NMR(400MHz，DMSO-d 6)：δ10.31(1H，s)；8.04(1H，s)；7.53(2H，d，J＝8.39Hz)；7.33(2H，d，J＝8.20Hz)；7.24(1H，s)；7.14(1H，d，J＝8.11Hz)；6.97(1H，d，J＝8.01Hz)；6.03(2H，d，J＝6.87Hz)；5.84(1H，d，J＝3.62Hz)；4.92(1H，s)；4.35(1H，s).
APCI-MS?m/z：309[MH +-H 2O]
The 5-[hydroxyl-(3 '-nitro-xenyl-4-yl)-methyl]-5-methyl-imidazolidine-2, the 4-diketone
Figure A0281004102184
1H?NMR(400MHz，DMSO-d 6)：δ10.18(1H，s)；8.41(1H，t，J＝8.41Hz)；8.20(1H，m)；8.15(1H，m)；8.12(1H，s)；7.73(3H，m)；7.41(2H，d，J＝8.20)；5.97(1H，d，J＝4.39Hz)；4.68(1H，d，4.58Hz)；1.43(3H，s).
APCI-MS?m/z：342.1[MH +]
Embodiment 33
These compounds are synthetic according to the method E (acid amides coupling) in path 4 (providing in the top description).These compounds are by following general method preparation.All amine that use in the coupling are commercial.
Figure A0281004102191
To 4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-the 0.3M solution of xenyl-4-carboxylic acid in 1-Methyl-2-Pyrrolidone (50 μ L) in, add 1-ethyl-3 (3-dimethyl aminopropyl) carbon imide (carbdiimide) hydrochloride (1.3eq, 45 μ L, 0.5M in 1-Methyl-2-Pyrrolidone), I-hydroxybenzotriazole (1.7eq, 51 μ L 0.5M, in 1-Methyl-2-Pyrrolidone), N, N-diisopropyl ethyl amine (1eq, 20 μ L 1M are at 1-Methyl-2-Pyrrolidone) and corresponding amine (2eq, 100 μ L 0.3Min 1-Methyl-2-Pyrrolidones).This reaction mixture at room temperature stirred spend the night.By preliminary HPLC-C 18Purifying.
4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-4-carboxylic acid (2-hydroxyl-ethyl)-methyl-acid amides
APCI-MS?m/z：398.1[MH +]
The 5-{ hydroxyl-[4 '-(morpholine-4-carbonyl)-xenyl-4-yl]-methyl }-5-methyl-imidazolidine-2, the 4-diketone
APCI-MS?m/z：410.1[MH +]
4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-4-carboxylic acid methyl-(1-methyl-tetramethyleneimine-3-yl)-acid amides
APCI-MS?m/z：437.1[MH +]
4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-4-carboxylic acid (2-morpholine-4-base-ethyl)-acid amides
APCI-MS?m/z：453.1[MH +]
4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-4-carboxylic acid (2-methoxyl group-ethyl)-acid amides
Figure A0281004102204
APCI-MS?m/z：398.1[MH +]
The 5-{ hydroxyl-[4 '-(tetramethyleneimine e-1-carbonyl)-xenyl-4-yl]-methyl }-5-methyl-imidazolidine-2, the 4-diketone
Figure A0281004102211
APCI-MS?m/z：394.1[MH +]
4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-4-carboxylic acid (2-cyano group-ethyl)-methyl-acid amides
APCI-MS?m/z：407.1[MH +]
4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-4-carboxylic acid methyl-styroyl-acid amides
APCI-MS?m/z：458.1[MH +]
4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-4-carboxylic acid (4-cyano group-cyclohexyl)-methyl-acid amides
Figure A0281004102221
APCI-MS?m/z：461.1[MH +]
The 5-{ hydroxyl-[4 '-(4-methylol-piperidines-1-carbonyl)-xenyl-4-yl]-methyl }-5-methyl-imidazolidine-2, the 4-diketone
Figure A0281004102222
APCI-MS?m/z：438.1[MH +]
4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-4-carboxylic acid [3-(2-oxo-tetramethyleneimine-1-yl)-propyl group]-acid amides
Figure A0281004102223
APCI-MS?m/z：465.1[MH +]
4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-4-carboxylic acid cyclopentyl amide
APCI-MS?m/z：408.1[MH +]
4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-4-carboxylic acid (1-phenyl-ethyl)-acid amides
Figure A0281004102231
APCI-MS?m/z：444.1[MH +]
4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-4-carboxylic acid (pyridine 4-ylmethyl)-acid amides
Figure A0281004102232
APCI-MS?m/z：431.1[MH +]
4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-4-carboxylic acid benzyl acid amides
APCI-MS?m/z：430.1[MH +]
4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-4-carboxylic acid cyclopropyl amide
Figure A0281004102241
APCI-MS?m/3?80.1[MH +]
4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-4-carboxylic acid 4-methoxyl group-benzyl acid amides
APCI-MS?m/z：460.1[MH +]
4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-4-carboxylic acid (3-imidazoles-1-base-propyl group)-acid amides
APCI-MS?m/z：448.1[MH +]
N-{4-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-phenyl }-benzamide
5-[hydroxyl-(4-nitro-phenyl)-methyl]-5-methyl-imidazolidine-2, the 4-diketone synthesizes (APCI-MS m/z:268.8[MH according to the path of describing among the embodiment 24 according to method C +]).Provide corresponding amine 5-[(4-amino-phenyl by the Pd in the ethanol (O) catalytic hydrogenation)-hydroxyl-methyl]-5-methyl-imidazolidine-2, the 4-diketone.
(APCI-MS m/z:218.0[MH +] (H20)) .5-[(4-amino-phenyl)-hydroxyl-methyl]-5-methyl-imidazolidine-2, the 4-diketone is final and phenylformic acid coupling according to top path (method E), obtains title compound.
APCI-MS?m/z：240.0[MH +]
Embodiment 34
Enantiomer, wherein by following fractionation 4 '-method that (hydroxyl-(4-methyl-2,5-dioxo alkyl imidazole-4-yl)-methyl) biphenyl-4-nitrile is described splits.
4 '-(hydroxyl-(4-methyl-2,5-dioxo alkyl imidazole-4-yl)-methyl) biphenyl-4-nitrile
Chromatogram splits:
With 0.10g of diastereomer pure 4 '-(hydroxyl-(4-methyl-2,5-dioxo alkyl imidazole-4-yl)-methyl) biphenyl-4-nitrile is dissolved in 76 mL absolute ethanol/isohexanes (75: 25) and by 0.45 μ m nylon filter and filters.With chirality pillar (ChiralpakAD-H (2cm ID * 25cm L)) that UV-detector (254nm) links to each other with run tank on inject 5.0mL repeatedly.Separate and under the 8.0mol/min flow velocity, to carry out with absolute ethanol/isohexane (75: 25), and the pure optically active enantiomorph of wash-out after about 15 and 21 minutes respectively.The cut that will contain identical enantiomer merges, concentrates, and assesses its optical purity (referring to following) by chiral chromatography.
Enantiomer A (" preceding " cut)
Output: 0.047g, white solid
Chiral chromatographyIn (Chiralpak AD-H (0.45cm I.D * 25cm L) is in 0.43mL/min absolute ethanol/isohexane (75: 25))
The residence time: 11.4 minutes
Optical purity: 99.9%e.e (no mapping isomer B exists)
1H NMR (CD 3OD) δ 1.60 (s, 3H), 4.84 (m is fogged by water is unimodal, 1H), 7.50 (d, 2H, J=8Hz), 7.62 (d, 2H; J=8Hz) and 7.79 (m, 4H) ppm.
Enantiomer B (" back " cut)
Output: 0.040g white solid
Chiral chromatographyUnder (Chiralpak AD-H (0.45cm I.D * 25cm L) is in 0.43mL/min absolute ethanol/isohexane (75: 25))
The residence time: 18.0 minutes
Optical purity: 99.0%e.e (0.50% enantiomer A existence)
1H NMR (CD 3OD) δ 1.60 (s, 3H), 4.84 (m is fogged by water is unimodal, 1H), 7.50 (d, 2H, J=8Hz), 7.62 (d, 2H; J=8Hz) and 7.79 (m, 4H) ppm.
N-(4 '-(hydroxyl-(4-methyl-2,5-dioxo alkyl imidazole-4-yl)-methyl) biphenyl-3-yl) ethanamide
Figure A0281004102261
Chromatogram splits:
With the pure N-of 0.040g diastereomer (4 '-(hydroxyl-(4-methyl-2,5-dioxo alkyl imidazole-4-yl)-and methyl) biphenyl-3-yl) ethanamide is dissolved in 224mL absolute ethanol/isohexane (71: 29), and according to using 6.0mL/min absolute ethanol/isohexane (50: 50) to separate as elutriant as mentioned above
Enantiomer A (" preceding " cut)
Output: 0.019g white solid
Chiral chromatographyUnder (Chiralpak AD-H (0.45cm I.D * 25cm L) is in 0.43mL/min absolute ethanol/isohexane (50: 50))
The residence time: 10.4 minutes
Optical purity: 99.9%e.e (no mapping isomer B exists)
1H NMR (CD 3OD) δ 1.60 (s, 3H), 2.14 (s, 3H), 4.82 (m is fogged by water is unimodal, 1H), 7.33 (m, 1H), 7.36 (t, 1H, J=8Hz), 7.44 (d, 2H, J=8Hz), 7.50 (m, 1H), 7.54 (d, 2H; J=8Hz) and 7.82 (m, 1H) ppm.
Enantiomer B (" back " cut)
Output: 0.018g white solid
Chiral chromatography(Chiralpak AD-H (0.45cm I.D * 25cm L) at 0.43mL/min absolute ethanol/isohexane (50: 50))
The residence time: 14.8 minutes
Optical purity: 99.6%e.e (0.20% enantiomer A existence)
1H NMR (CD 3OD) δ 1.60 (s, 3H), 2.14 (s, 3H), 4.82 (m is fogged by water is unimodal, 1H), 7.33 (m, 1H), 7.36 (t, 1H, J=8Hz), 7.44 (d, 2H, J=8Hz), 7.50 (m, 1H), 7.54 (d, 2H; J=8Hz) and 7.82 (m, 1H) ppm.
5-(biphenyl-4-base-hydroxyl-methyl)-imidazolidine-2, the 4-diketone.
Figure A0281004102271
Chromatogram splits:
Be separated in Gilson HPLC system (column:CHIRALPAK AD, 2.0 * 25cm.Solvent: carry out isohexane/EtOH=25/75. flow=6.0mL/min.UV=254nm.Inj volume=3.0mL).24mg racemize material is dissolved among 24mL isohexane/EtOH=25/75.Collection has the enantiomer of Rt=17.72min and 20.47min and desolvates by evaporating to remove.(pillar: CHIRALPAK AD, 0.46 * 25cm.Solvent: isohexane/EtOH=25/75. flow=0.5mL/min.UV=254nm) removes and desolvates with following GilsonHPLC system.Enantiomer: 9mg faster, Rt=10.12min, ee=99.9%.Slower enantiomer: 7mg, Rt=11.78min, ee=99.2%.
Embodiment 35
Below compound, by with embodiment 24 in the similar approach preparation described.
5-[(9H-fluorenes-2-yl)-hydroxyl-methyl]-imidazolidine-2, the 4-diketone
Figure A0281004102281
APCI-MS?m/z：277[MH+-H2O]
(3-{4-[(4 '-fluoro-xenyl-4-yl)-hydroxyl-methyl]-2,5-dioxo-imidazolidine-4-yl }-propyl group)-the carboxylamine benzyl ester
Figure A0281004102282
1H?NMR(400MHz，DMSO-d 6)：δ10.20(1H，s)；8.53(1H，d，J＝4.01Hz)；8.01(1H，s)；7.69(2H，m)；7.56(2H，d，J＝8.39Hz)，7.30(9H，m)，5.90(1H，d，J＝4.20Hz)，4.99(2H，s)4.64(1H，d，J＝4.20Hz)；2.98(2H，m)，1.97(1H，m)，1.72(1H，m)，1.42(1H，m)，1.22(1H，m).
APCI-MS?m/z：492.2[MH +].
5-(3-amino-propyl group)-5-[(4 '-fluoro-xenyl-4-yl)-hydroxyl-methyl]-imidazolidine-2, the 4-diketone
By above-mentioned (3-{4-[(4 '-fluoro-xenyl-4-yl)-hydroxyl-methyl]-2,5-dioxo-imidazolidine-4-yl }-propyl group)-the carboxylamine benzyl ester is by the known standard method preparation of those skilled in the art.
APCI-MS?m/z：358.1[MH +].
5-[hydroxyl-(4 ' methoxyl group-xenyl-4-yl)-methyl]-5-methyl sulfenyl methyl-imidazolidine-2, the 4-diketone
By 4 '-methoxyl group-xenyl-4-aldehyde (carbaldehyde) (table 3, method B) and 5-methyl sulfenyl methyl-imidazolidine-2,4 diketone (table 2, method A) be according to method C, embodiment 24 preparations.
1H?NMR(400MHz，DMSO-d 6)：δ10.25(1H，s)；8.16(1H，s)；7.59(2H，d，J＝8.77Hz，)，7.53(2H，d，J＝8.20Hz)；7.31(2H，d，J＝8.20Hz)；6.99(2H，d，J＝8.77Hz)；5.98(1H，d，J＝4.20Hz)；4.71(1H，d，J＝4.01Hz)；3.77(3H，s)；3.16(1H，d，J＝14.31Hz9，2.92(1H，d，J＝14.31Hz)，2.11(3H，s).
APCI-MS?m/z：373.1[MH +]
The 5-[hydroxyl-(4 '-methoxyl group-xenyl-4-yl)-methyl]-5-pyridine-2-ylmethyl-imidazolidine-2, the 4-diketone
By 4 '-methoxyl group-xenyl-4-aldehyde (carbaldehyde) (table 3, method B) and commercial 5-pyridine-2-ylmethyl-imidazolidine-2,4, according to method C, embodiment 24 preparations.
Figure A0281004102292
1H?NMR(400MHz，DMSO-d 6)：δ10.00(1H，s)；8.53(1H，d，J＝4.01Hz)；8.13(1H，s，)；7.91(1H，s)；7.58(2H，m)；7.53(2H，m)；7.38(4H，m)，7.00(2H，m)，6.11(1H，s)4.81(1H，s)；3.48(2H，m).
APCI-MS?m/z：404.3[MH +].
5-[hydroxyl-(4-pyrazine-2-base-phenyl)-methyl]-5-methyl-imidazolidine-2, the 4-diketone
By commercial 4-pyrazine-2-base-phenyl aldehyde and 5-methyl-glycolylurea, according to method C, embodiment 24 preparations.
APCI-MS?m/z：299[MH +].
5-{3-[4-(5-chloro-pyridine-2-base oxygen base)-phenyl]-1-hydroxyl-propyl group }-5-methyl-imidazolidine-2, the 4-diketone
3-[4-(5-chloro-pyridine-2-base oxygen base)-phenyl]-third-1-alcohol
Will be in N-methyl-pyrrolidone (10ml) blended 3-(4-hydroxy phenyl)-propyl alcohol (768.5,5.05mmol), 2, (934.8mg, 6.32mmol), (2.48g 7.60mmol) stirs and heating (100 ℃) 20 novels cesium carbonate 5-two chloro-pyridines.Be distributed in ethyl diacetate (100ml) with this flask cooling and with material, between di-tert-butyl ether (100ml) and the water (300ml).With (3 * 30ml) washings of organic phase water.Evaporation, (1.502g 5.70mmol), is yellow oil, 113% yield to obtain thick title compound.Purity is analyzed according to TLC.
APCI-MS?m/z：264[MH +]
3-[4-(5-chloro-pyridine-2-base oxygen base)-phenyl]-propionic aldehyde
Will-[4-(5-chloro-pyridine-2-base oxygen base)-phenyl]-(267mg, 1.0mmol) (302mg 1.4mmol) stirred 2 hours in methylene dichloride (20ml, exsiccant molecular sieve) third-1-alcohol with the chloropyridine father-in-law.Flash chromatography purifying (SiO2, methylene chloride: gradient to 100/5), (169mg 0.65mmol), is oily matter, yield 65% yield to obtain title compound.
APCI-MS?m/z：262[MH +]
5-{3-[4-(5-chloro-pyridine-2-base oxygen base)-phenyl]-1-hydroxyl-propyl group }-5-methyl-imidazolidine-2,4-two Ketone
With 3-[4-(5-chloro-pyridine-2-base oxygen base)-phenyl]-propionic aldehyde and commercial 5-methyl-glycolylurea be used for according to method C embodiment 24 synthesising title compounds.
Figure A0281004102311
APCI-MS?m/z：376.0[MH +].
5-{[4-(5-chloro-pyridine-2-base oxygen base)-phenyl]-hydroxyl-methyl }-5-methyl-imidazolidine-2, the 4-diketone
4-(the 5-chloro-is than pyridine-2-base oxygen base)-phenyl aldehyde
Will be in N-methyl-pyrrolidone (10ml) blended 4-hydroxyl-phenyl aldehyde (620.9mg, 5.08mmol), (2.6g, 7.98mmol) and 2, (947mg 6.40mmol) stirs and heating (75 ℃) 16 hours 5-two kloro pyridines cesium carbonate.Lcms analysis shows the formation few products.Further be reflected at high temperature (150 ℃) and carried out 6 hours, to increase the product that forms.With flask cooling and with material at ethyl diacetate (100ml), distribution between ether r (100ml) and the water (200ml).With (3 * 30ml) washings of organic phase water.Evaporate and flash distillation gas-chromatography (SiO 2, methylene chloride: gradient to 100/4), obtain 4-(5-chloro-pyridine-2-base oxygen base)-phenyl aldehyde (181mg, 0.77mmol), yield 15.2%.
1H?NMR(400MHz，DMSO-d 6)：δ9.98(1H，s)；8.27(1H，d)；8.04(1H，dd)；7.97(2H，d)；7.35(2h，d)；7.23(1H，d).
APCI-MS?m/z：234[MH +]
5-{[4-(5-chloro-pyridine-2-base oxygen base)-phenyl]-hydroxyl-methyl }-5-methyl-imidazolidine-2, the 4-diketone
4-(5-chloro-pyridine-2-base oxygen base)-phenyl aldehyde and commercial 5-methyl-glycolylurea are used for according to method C embodiment 24 synthesising title compounds.
Figure A0281004102312
APCI-MS?m/z：348[MH +].
Embodiment 36
5-[(3 '-amino-xenyl-4-yl)-hydroxyl-methyl]-5-methyl-imidazolidine-2, the 4-diketone
By the 5-[hydroxyl of describing among the embodiment 31-(3 '-nitro-xenyl-4-yl)-methyl]-5-methyl-imidazolidine-2, the 4-diketone is by the known standard method preparations of those skilled in the art (Pd (O) catalytic hydrogenation in ethanol).
Figure A0281004102321
APCI-MS?m/z：312.1[MH +]
Embodiment 37
Below compound according to following synthetic N-{4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine (imidazolin)-4-the yl)-methyl]-xenyl-3-yl that is used for-the path preparation of Toluidrin.
N-{4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine (imidazolin)-4-yl)-methyl]-xenyl-3-yl }-Toluidrin
With methane sulfonyl chloride (10ul 0.165mmol) is added dropwise to 5-[(3 '-amino-xenyl-4-yl)-hydroxyl-methyl]-5-methyl-imidazolidine-2, (41mg is 0.132mmol) in the solution in pyridine (1ml) for the 4-diketone.The gained mixture was at room temperature stirred 6 hours.Add entry 15ml) and with this aqueous mixture EtOAc (3 * 10ml) extractions.With the EtOAc extract drying (MgSO that merges 4) and under reduced pressure concentrate, obtain thick product.The HPLC (with acetonitrile/water (0.1% trifluoroacetic acid) wash-out) of preliminary on Chromasil C18 pillar, obtain 0mg (80% yield) title compound N-{4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-3-yl }-Toluidrin.
1H?NMR(400MHz，DMSO-d 6)：δ10.17(1H，s)；9.79(1H，s)；8.10(1H，s，)；7.57(2H，d，J＝8.39Hz)；7.40(5H，m)；7.19(1H，m)；7.25(2H，d，J＝8.39Hz)；7.20(1H，m)；5.92(1H，m)；4.65(1H，s)；3.01(3H，s)；1.42(3H，s，).
APCI-MS?m/z：390.1[MH +]
N-{4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine (imidazolin)-4-yl)-methyl]-xenyl-3-yl }-propionic ester
1H?NMR(400MHz，DMSO-d 6)：δ10.17(1H，s)；9.90(1H，s)；8.09(1H，s，)；7.90(1H，s)；7.51(3H，m)；7.32(4H，m)；5.92(1H，d，J＝4.39Hz)；4.65(1H，d，J＝4.39Hz)；2.32(1H，q，J＝7.44Hz)；1.42(3H，s)；1.08(3H，t，J＝7.53Hz).
APCI-MS?m/z：368.1[MH +].
N-{4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-methyl]-xenyl-3-yl }-isobutyramide
Figure A0281004102332
1H?NMR(400MHz，DMSO-d 6)：δ10.15(1H，s)；9.87(1H，s)；8.09(1H，s，)；7.92(1H，s)；7.52(3H，m)；7.33(4H，m)；5.92(1H，d，J＝4.39Hz)；4.65(1H，d，J＝4.39Hz)；2.59(1H，m)；1.42(3H，s)；1.10(6H，d，J＝6.87Hz).
APCI-MS?m/z：382.1[MH +].
N-{4 '-[hydroxyl-(4-methyl-2,5-dioxo-imidazolidine (imidazolin)-4-yl)-methyl]-xenyl-3-yl }-2,2-dimethyl propylene acid amides
1H?NMR(400MHz，DMSO-d 6)：δ10.15(1H，s)；9.23(1H，s)；8.09(1H，s，)；7.93(1H，s)；7.58(3H，m)；7.33(4H，m)；5.91(1H，d，J＝4.39Hz)；4.65(1H，d，J＝4.39Hz)；1.42(3H，s)；1.22(9H，s).
APCI-MS?m/z：396.2[MH +].
Embodiment 38
5-[(4 '-chlordiphenyl-4-yl) methoxymethyl]-5-Methylimidazole alkane-2, the 4-diketone
Figure A0281004102341
4-chloro-4 '-(2-nitro propenyl) biphenyl
4-(4-chloro-phenyl-) phenyl aldehyde (0.66g, 3.0mmo1), nitroethane (2mL), volatile salt (3.5g) and glacial acetic acid (17mL) were stirring 20 hours under nitrogen atmosphere under 82 ℃.With volatile matter evaporation, yellow residue is absorbed as in the ether and wash with water once.Wash with aqueous phase separation and with ether.With organic phase water and the salt water washing that merges, dry on anhydrous sodium sulphate, filter and concentrate with silicon-dioxide (3g) by rotary evaporation.The exsiccant resistates is imposed on the silicon-dioxide pillar.With ethyl acetate/normal heptane ((1: 20) is to (1: 8)) wash-out, obtain 0.50g (61% yield) title compound, be yellow (wellow) crystal.Mp.113.8-114.3 ℃ (not proofreading and correct).
FT-IR(ATR)ν?1647(w)，1504(str)，1484(str)，1320(v?str)，812(str)cm -1.
1H?NMR(300MHz，CDCl 3)δ2.50(d，3H，J＝1Hz)，7.44(d，2H，J＝9Hz)，7.52(d，2H，J＝9Hz)，7.55(d，2H，J＝9Hz)，7.65(d，2H，J＝9Hz)and?8.12(br?s，1H)ppm.
13C?NMR(100MHz，CDCl 3)δ14.2，127.2，128.2，129.1，130.5，131.5，132.9，134.1，138.1，141.3?and?147.6ppm.
4-chloro-4 '-(1-methoxyl group-2-nitro propyl group) biphenyl
With 4-chloro-4 '-(2-nitro propenyl) biphenyl (0.39g, 1.3mmol), sodium methylate (4.0mmol; Newly prepare by 0.091g sodium and dry methyl alcohol) and anhydrous 1,2-glycol dimethyl ether (3.0mL) stirred 3 hours down at 22 ℃ under nitrogen atmosphere, be used in 10% acetate acidifying in the methyl alcohol (4mL), be concentrated into drying by rotary evaporation and be absorbed into then in ethyl diacetate and the water.Wash once with aqueous phase separation and with ethyl acetate.With the organic phase salt water washing that merges, dry on anhydrous sodium sulphate, filter and concentrate with silicon-dioxide (3g) by rotary evaporation.The exsiccant resistates is imposed on the silicon-dioxide pillar.((1: 3) to (1: 1) wash-out obtains 0.40g (95% yield) title compound, is white solid with methylene dichloride/normal heptane.
FT-IR(ATR)ν?1552(v?str)，1485(str)，1092(str)，814(str)cm -1.
1H NMR (400MHz, CDCl 3) δ 1.30 (d, 1.3H, J=7Hz) 1.56 (d, 1.7H, J=7Hz), 3.22 (s, 1.2H), 3.32 (s, 1.8H), 4.56 (d, 1.2H, J=10Hz), 4.63 (mc, 1.8H), 4.76 (mc, 1.2H), 4.88 (d, 1.8H, J=5Hz) and 7.38-7.62 (m ' s, 8H) ppm. 13CNMR (100MHz, CDCl 3) δ 13.0,16.3,57.0,57.7,83.5,84.8,86.9,87.5,127.3,127.5,128.3,129.0,129.1,132.7,133.7,133.9,135.1,135.9,138.7,138.8,140.4,140.9ppm (diastereomer signal).
1-(4 '-chlordiphenyl-4-yl)-1-methoxy propyl-2-ketone
With 4-chloro-4 '-(0.123g, 0.40mmol), the mixture of exsiccant methylene dichloride (2.8mL) and the final 3_ molecular sieve (0.040g) that grinds cools off on ice bath under argon gas atmosphere (1-methoxyl group-2-nitro propyl group) biphenyl.(0.170g 0.48mmol) adds during this refrigerative stirs the mixture by part will to cross the ruthenic acid tetrapropyl ammonium.After adding is finished, remove ice bath, and this mixture was stirred 4.0 hours at 22 ℃.Add ether (30mL) and the dark suspension of gained is filtered by Celite.This clear solution is concentrated with silicon-dioxide (4g) by rotary evaporation.The exsiccant resistates is imposed on the silicon-dioxide pillar.((1: 2) to (2: 1) wash-out obtains 0.052g (47% yield) title compound, is white solid with methylene dichloride/normal heptane.FT-IR(ATR)ν?1716(v?str)，1485(str)，1093cm -1(v?str).
1H?NMR(300MHz，CDCl 3)δ2.16(s，3H)3.42(s，3H)，4.69(s，1H)，7.40(d，2H，J＝9Hz)，7.46(d，2H，J＝8Hz)，7.51(d，2H，J＝9Hz)and?7.56(d，2H，J＝8Hz)ppm. 13C?NMR(100MHz，CDCl 3)δ25.1，57.3，89.1，127.2，127.4，128.2，128.8，133.5，135.1，138.8，140.1?and?206.4ppm
5-[(4 '-chlordiphenyl-4-yl) methoxymethyl]-5-Methylimidazole alkane-2, the 4-diketone
With 1-(4 '-chlordiphenyl-4-yl)-1-methoxy propyl-2-ketone (0.051g, 0.19mmol), volatile salt (0.089g, 0.93mmol), potassium cyanide (0.025g, 0.37mmol; ) and 50% aqueous ethanol (1.4mL) in the pipe (4.5mL) of sealing, stirred 19 hours down at 87 ℃ (oil bath temperatures).With solvent evaporation, add entry so that volume is about 20mL,, and thick product is absorbed in the ethyl diacetate (50mL) pH regulator to 3 with glacial acetic acid.With organic phase once with the salt water washing, dry on anhydrous sodium sulphate, filter and concentrate by rotary evaporation, obtain 0.065g (100% yield) title compound, be white solid. 1H?NMR(400MHz，DMSO-d 6)δ1.06(s，2H)，1.43(s，1H)，3.07(s，2H)，3.17(s，1H)，4.33(s，0.7H)，4.34(s，0.3H)，7.30-7.75(m′s，8.7H)，8.24(br?s，0.3H)，10.26(br?s，0.3H)and?10.56(br?s，0.7H)ppm.
13C NMR (100MHz, DMSO-d 6) δ 20.2,21.1,56.6,57.0,65.5,66.2,84.2,84.9,125.8,126.1,128.20,128.22,128.74,128.76,128.79,128.9,132.2,135.3,135.4,138.2,138.3,138.3,138.4,156.1,156.9,175.9 and 177.1ppm (diastereomer signal).
Embodiment 39
5-[hydroxyl-(4-quinoline-3-base-phenyl)-methyl-imidazolidine-2, the 4-diketone
This compound is according to J.Org.Chem.2001, and 66,1500-1502, commercial 3-bromo-quinoline and above-mentioned 5-[hydroxyl-(4-iodo-phenyl)-methyl]-imidazolidine-2, the 4-diketone is synthetic.
APCI-MS?m/z：348.2[MH +]
Embodiment 40 to 61: the preparation initial substance
According to following path 4, prepare glycolylurea 5 by general amino acid 3 and isolating intermediate 4 by two steps.
Route 4
Figure A0281004102362
Table 1 has been listed some synthetic initial substance 5.The general method of preparation is as follows, and (5.1g, 63mmol) slurry in water (75ml) heated about 1 hour down at 80 ℃ with amino acid 3 (25mmol) and potassium cyanate.This clear solution is cooled to 0 ℃ also is acidified to pH about 1 with concentrated hydrochloric acid (aq).Gained white depositions 4 was heated about 0.5-1 hour under refluxing, then in cooled on ice.Do not reach fully after 1 hour in heating in some cases and transform.In these cases, thick product is handled under same paths once more.White solid is filtered, wash with water, dry and by HNMR and lcms analysis.
Table 1: initial substance
Compound in the route 4 Yield (%) ??APCI-MS ?m/z：[MH +]
5-(4-chloro-benzyl)-imidazolidine-2, the 4-diketone ????87 ????224.9
[3-(2,5-dioxo-imidazolidine-4-yl)-propyl group]-carboxylamine benzyl ester ????50 ????292.0
5-isobutyl--imidazolidine-2, the 4-diketone ????85 ????157.0
5-methyl sulfenyl methyl-imidazolidine-2, the 4-diketone ????45 ????161.0
5-sec-butyl-imidazolidine-2, the 4-diketone ????52 ????157.0
5-(2-hydroxyl-ethyl)-imidazolidine-2, the 4-diketone ????36
Embodiment 40
5-[hydroxyl-(4-iodo-phenyl)-methyl]-5-methyl-imidazolidine-2, the 4-diketone
Figure A0281004102371
With 4-iodo-phenyl aldehyde (9.280g, 40.0mmol), 5-methyl-glycolylurea (4.564g, 40.0mmol) and 45% trimethylamine aqueous solution (6.40ml, 40.0mmol) in ethanol (60ml) and water (40ml) under argon gas atmosphere reflux 20.Form white depositions.After at room temperature cooling off about 15 minutes, by filtering the collecting precipitation thing, (50%, 50ml), water (50ml) and diethyl ether (50ml) order are washed with ethanol.By the air suction dried, (7.968g 23.0mol), obtains 57.5% yield, is the white solid of pure racemic modification form to obtain title compound.
1H?NMR(300MHz，DMSO-d 6)：δ10.19(1H，s)；8.08(1H，s)；7.64(2H，d，J＝8.6Hz)；7.07(2H，d，J＝8.4Hz)；5.98(1H，d，J＝4.5Hz)；4.57(1H，d，J＝4.3Hz)；1.40(3H，s).
APCI-MS?m/z：346.9[MH +].
Chromatogram splits:
With the pure 5-of 0.158g diastereomer (hydroxyl-(4-iodine substituted phenyl)-methyl)-5-methyl-imidazolidine-2, the part of 4-diketone is dissolved in 205mL absolute ethanol/isohexane (50: 50), and filters by 0.45 μ m nylon filter.With the duplicate injection of 5.0mL volume with chirality pillar (Chiralpak AD-H (2cm ID * 25cm L)) that UV detector (254nm) links to each other with run tank on.Separate under the 6.0mL/min flow velocity as elutriant and with pure enantiomer wash-out with absolute ethanol/isohexane (50: 50).The part that will contain identical enantiomer merges, and concentrates and by chiral chromatography assessment (face as follows).
Enantiomer A (" preceding " cut)
Output: 0.068g white plates
Chiral chromatography(Chiralpak AD-H (0.45cm I.D * 25cm L) at 0.43mL/min absolute ethanol/isohexane (50: 50))
The residence time: 10.5 minutes
Optical purity: 99.9%e.e (no mapping isomer B exists)
Enantiomer B (" back " cut)
Output: 0.071g white plates
Chiral chromatography(Chiralpak AD-H (0.45cm I.D * 25cm L) at 0.43mL/min absolute ethanol/isohexane (50: 50))
The residence time: 12.2 minutes
Optical purity: 99.6%e.e (0.24% enantiomer B existence)
The NMR spectrum of this pure enantiomer is complementary with pure racemic modification.
The following examples prepare according to the program among the embodiment 40.If not explanation in addition, final compound is represented the mixing of four kinds of steric isomers.Column chromatography is used for final purifying or racemic modification separation.
Embodiment 41
5-[(4-chloro-phenyl)-hydroxyl-methyl)]-imidazolidine-2, the 4-diketone
Racemic modification A
1H?NMR(400MHz，DMSO-d 6)：10.32(1H，s)；8.07(1H，s)；7.37(2H，d，J＝8.5Hz)；7.30(2H，d，J＝8.5Hz)；5.94(1H，d，J＝3.9Hz)；4.92(1H，t，J＝3.2Hz)；4.35(1H，dd，J＝3.1，1.0Hz).
13C?NMR(400MHz，DMSO-d 6)：173.00；157.36；138.41；131.98；128.86；127.52；71.65；63.88.
APCI-MS?m/z：241[MH+].
Racemic modification B
1H?NMR(400MHz，DMSO-d 6)：10.53(1H，s)；7.54(1H，s)；7.42-7-37(4H，m)；5.83(1H，d，J＝5.6Hz)；4.91(1H，dd，J＝5.6，2.6Hz)；4.23(1H，dd，J＝2.6，1.5Hz).
13C?NMR(400MHz，DMSO-d 6)：173.97；158.04；140.62；131.67；128.15；127.89；70.08；63.93.
APCI-MS?m/z：241[MH+].
Embodiment 42
5-[(4-chloro-phenyl)-hydroxyl-methyl]-5-phenyl-imidazolidine-2, the 4-diketone
APCI-MS?m/z：317.1[MH+].
Embodiment 43
5-[(4-cyano group-phenyl)-hydroxyl-methyl]-5-isobutyl--imidazolidine-2, the 4-diketone
APCI-MS?m/z：288.1[MH+].
Embodiment 44
5-[(4-trifluoromethyl-phenyl)-hydroxyl-methyl]-imidazolidine-2, the 4-diketone
APCI-MS?m/z：275.1[MH+].
Embodiment 45
5-[(3-trifluoromethyl-phenyl)-hydroxyl-methyl]-imidazolidine-2, the 4-diketone
APCI-MS?m/z：275.2[MH+].
Embodiment 46
5-[(2-trifluoromethyl-phenyl)-hydroxyl-methyl]-imidazolidine-2, the 4-diketone
Figure A0281004102403
APCI-MS?m/z：275.1[MH+].
Embodiment 47
5-[(4-trifluoromethoxy-phenyl)-hydroxyl-methyl]-imidazolidine-2, the 4-diketone
APCI-MS?m/z：291.3[MH+].
Embodiment 48
5-[(3-chloro-phenyl)-hydroxyl-methyl]-imidazolidine-2, the 4-diketone
Figure A0281004102411
APCI-MS?m/z：241.0[MH+].
Embodiment 49
5-[(2-chloro-phenyl)-hydroxyl-methyl]-imidazolidine-2, the 4-diketone
Figure A0281004102412
APCI-MS?m/z：241.0[MH+].
Embodiment 50
5-[(4-chloro-3-fluoro-phenyl)-hydroxyl-methyl]-imidazolidine-2, the 4-diketone
Figure A0281004102413
APCI-MS?m/z：259.0[MH+]
Embodiment 51
5-[(4-chloro-3-fluoro-phenyl)-hydroxyl-methyl]-5-methyl-imidazolidine-2, the 4-diketone
Figure A0281004102414
APCI-MS?m/z：272.9[MH+]
Embodiment 52
5-[(4-chloro-3-fluoro-phenyl)-hydroxyl-methyl]-5-isobutyl--imidazolidine-2, the 4-diketone
Figure A0281004102421
APCI-MS?m/z：315.9[MH+]
Embodiment 53
5-(1-hydroxyl-3-phenyl-allyl group)-5-methyl-imidazolidine-2, the 4-diketone
1HNMR(400MHz，DMSO-d 6)：δ10.45(1H，s)；7.88(1H，s)；7.38-7.22(5H，m)；6.54(1H，d，J＝16.1Hz)；6.22(1H，dd，J＝7.3，7.6Hz)；5.56(1H，d，J＝4.5Hz)；4.09(1H，d，J＝3.6，4.5Hz)；1.27(3H，s).
APCI-MS?m/z：247.1[MH +].
Embodiment 54
5-[hydroxyl-(4-iodo-phenyl)-methyl]-imidazolidine-2, the 4-diketone
1HNMR(300MHz，DMSO-d 6)：δ10.32(1H，s)；8.06(1H，s)；7.66(2H，d，J＝8.1Hz)；7.10(2H，d，J＝8.3Hz)；5.91(1H，d，J＝3.9Hz)；4.87(1H，t，J＝2.7Hz)；4.34(1H，d，J＝2.5Hz).
APCI-MS?m/z：333.1[MH +].
Embodiment 55
(3-{4-[hydroxyl-(4-iodo-phenyl)-methyl]-2,5-dioxo-imidazolidine-4-yl }-propyl group)-the carboxylamine benzyl ester
APCI-MS?m/z：524.1[MH +].
Embodiment 56
5-[(4-bromo-phenyl)-hydroxyl-methyl]-5-methyl-imidazolidine-2, the 4-diketone
By 4-bromo-phenyl aldehyde and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
1H?NMR(400MHz，DMSO-d 6)：δ10.18(1H，s)；8.08(1H，s)；7.46(2H，d，J＝8.4Hz)；7.20(2H，d，J＝8.4Hz)；5.99(1H，d，J＝4.4Hz)；4.59(1H，d，3.81Hz)；1.39(3H，s).
APCI-MS?m/z：298.9[MH +]
Embodiment 57
5-[(3,5-dimethyl-isoxazole-4-bases)-hydroxyl-methyl]-5-methyl-imidazolidine-2, the 4-diketone
By 3,5-dimethyl-isoxazoles-4-aldehyde (carbaldehyde) and 5-methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102433
APCI-MS?m/z：240[MH +]
Embodiment 58
5-[(4-bromo-phenyl)-hydroxyl-methyl]-5-methyl sulfenyl methyl-imidazolidine-2, the 4-diketone
By 4-bromo-phenyl aldehyde and 5-methyl sulfenyl methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102441
APCI-MS?m/z：347.1[MH +]
Embodiment 59
5-[(4-bromo-phenyl)-hydroxyl-methyl]-5-(2-hydroxyl-ethyl)-imidazolidine-2, the 4-diketone
By 4-bromo-phenyl aldehyde and 5-(2-hydroxyl-ethyl)-imidazolidine-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102442
APCI-MS?m/z：311.2[MH +-H 2O]
Embodiment 60
5-[(4-bromo-phenyl)-hydroxyl-methyl]-5-(4-chloro-benzyl)-imidazolidine-2, the 4-diketone
By 4-bromo-phenyl aldehyde and 5-(4-chloro-benzyl)-imidazolidine-2, the 4-diketone carries out aldol condensation production.
APCI-MS?m/z：411[MH +]
Embodiment 61
The 5-[(4-bromophenyl) hydroxyl-methyl]-5-pyridine-2-ylmethyl-imidazolidine-2, the 4-diketone
By 4-bromo-phenyl aldehyde and 5-pyridin-4-yl methyl-imidazolidine-2, the 4-diketone carries out aldol condensation production.
Figure A0281004102444
APCI-MS?m/z：378.1[MH +].

Claims (10)

1. hydrolyzable ester in an inhibitors of metalloproteinase compound that is used for the treatment of the disease that mediated by one or more metalloproteases or illness or acceptable salt of its medicine or the body, wherein this inhibitors of metalloproteinase compound comprises melts combine group and one or more other functional group or side chain, it is characterized in that the melts combine base has following general formula (I)
Figure A0281004100021
Wherein X is selected from NR1, O, S;
B is C or CH, and is the tie point of one or more other functional groups or side chain;
Y1 and Y2 are independently selected from O, S;
R1 is selected from H, alkyl, alkylhalide group.
2. hydrolyzable ester in inhibitors of metalloproteinase compound as claimed in claim 1 or the acceptable salt of its medicine or the body, it comprises the melts combine group of general formula (I), wherein X is NR1; At least one of Y1 and Y2 is O; R1 is H, (C1-6) alkyl or halo (C1-6) alkyl.
3. hydrolyzable ester in inhibitors of metalloproteinase compound as claimed in claim 1 or the acceptable salt of its medicine or the body, the melts combine group of its formula of (I) are-5 replacement 1-H, 3-H-imidazolidine-2,4-diketone.
4. hydrolyzable ester in inhibitors of metalloproteinase compound as claimed in claim 1 or the acceptable salt of its medicine or the body is used for the treatment of disease or illness by one or more matrix metalloproteinase mediations.
5. hydrolyzable ester in inhibitors of metalloproteinase compound as claimed in claim 4 or the acceptable salt of its medicine or the body is used for the treatment of by being selected from MMP12, MMP9, MMP13, MMP8, the disease or the illness of one or more enzyme mediations of MMP3.
6. hydrolyzable ester in inhibitors of metalloproteinase compound as claimed in claim 4 or the acceptable salt of its medicine or the body, wherein the inhibitors of metalloproteinase compound is
(a) compound of general formula I I
Figure A0281004100031
Wherein
X is selected from NR1, O, S;
Y1 and Y2 are independently selected from O, S;
Z is selected from O, S, SO, SO 2, SO 2N (R6), N (R7) SO 2, N (R7) SO 2N (R6);
M is 1 or 2;
A is selected from direct key, (C1-6) alkyl, (C1-6) haloalkyl or contains (C1-6) assorted alkyl that is selected from the heteroatom group of N, O, S, SO, SO2 or contains two heteroatom groups that are selected from N, O, S, SO, SO2 and opened by at least two carbon atoms separate;
R1 is selected from H, (C1-3) alkyl, alkylhalide group;
Each R2 and R3 are independently selected from H, halogen (preferred fluorine), alkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkaryl, alkyl-heteroaryl, assorted alkyl-aryl, assorted alkyl-heteroaryl, aryl-alkyl, aryl-assorted alkyl, heteroaryl-alkyl, heteroaryl-assorted alkyl, aryl-aryl, aryl-heteroaryl, heteroaryl-aryl, heteroaryl-heteroaryl, cycloalkyl-alkyl, Heterocyclylalkyl-alkyl, alkyl-cycloalkyl, alkyl-Heterocyclylalkyl;
Each R4 is independently selected from H, halogen (preferred fluorine), (C1-3) alkyl or alkylhalide group;
R6 is selected from H, alkyl, assorted alkyl, Heterocyclylalkyl, aryl, heteroaryl, alkaryl, alkyl-heteroaryl, assorted alkyl-aryl, assorted alkyl-heteroaryl, aralkyl, aryl-assorted alkyl, heteroaryl-alkyl, heteroaryl-assorted alkyl, aryl-aryl, aryl-heteroaryl, heteroaryl-aryl, heteroaryl-heteroaryl;
Each R2, R3 and R6 group can be chosen wantonly independently by one or more (preferred one) group and replace, these groups are selected from alkyl, assorted alkyl, aryl, heteroaryl, halogen, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, thiol, the alkyl sulfide hydroxyl, the aryl thiol, the alkyl sulfone, haloalkylsulfone, aryl sulfone, amino sulfone, N-alkylamino sulfone, N, N-dialkylamino sulfone, the amino sulfone of virtue, amino, the N-alkylamino, N, the N-dialkylamino, amido, the N-alkyl amido, N, N-dialkyl group amido, cyano group, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, amidino groups, N-aminosulfonyl-amidino groups, guanidine radicals, N-cyano group-guanidine radicals, the sulfo-guanidine radicals, 2-nitro-ethene-1, the 1-diamines, carboxyl, alkyl-carboxyl, nitro, carbamate;
R2 and R3 optionally can connect into and contain the ring that reaches 7 annular atomses, or R2 and R4 can connect into and contain the ring that reaches 7 annular atomses, or R2 and R6 can connect into and contain the ring that reaches 7 annular atomses, or R3 and R4 can connect into and contain the ring that reaches 7 annular atomses; Or R3 and R6 can connect into and contain the ring that reaches 7 annular atomses; Or R4 and R6 can connect into and contain the ring that reaches 7 annular atomses;
R5 contains one, two or three reach the monocycle of the ring structure of 7 annular atomses separately, two ring or three cyclic groups, they select cycloalkyl independently, aryl, Heterocyclylalkyl or heteroaryl, wherein each ring structure is optional is independently replaced by one or more substituting groups, these substituting groups are independently selected from halogen, hydroxyl, alkyl, alkoxyl group, halogenated alkoxy, amino, the N-alkylamino, N, the N-dialkylamino, alkyl sulfonyl amino, alkyl carboxyl amino, cyano group, nitro, thiol, the alkyl sulfide hydroxyl, alkyl sulphonyl, halogenated alkyl sulfonyl, the alkylamino alkylsulfonyl, carboxylicesters, the alkyl carboxylic acid ester, amino carboxyl, N-alkylamino-carboxyl, N, N-dialkylamino-carboxyl, any alkyl itself on wherein any substituting group can be chosen wantonly by one or more groups and replace, these groups are selected from halogen, hydroxyl, alkoxyl group, halogenated alkoxy, amino, the N-alkylamino, N, the N-dialkylamino, N-alkyl sulfonyl amino, N-alkyl carboxyl amino, cyano group, nitro, thiol, the alkyl sulfide hydroxyl, alkyl sulphonyl, N-alkylamino alkylsulfonyl, carboxylicesters, alkyl carboxyl, amino carboxyl, N-alkylamino carboxyl, N, N-dialkylamino carboxyl, carbamate;
When R5 is two rings or during three cyclic groups, each ring structure by direct key ,-mix alkyl, (C1-6) alkenyl, (C1-6) alkynyl, sulfone, CO, NCO, CON, NH, S, C (OH) of O-, (C1-6) alkyl, (C1-6) haloalkyl, (C1-6) be connected with the adjacent ring structure or condense with the adjacent ring structure;
R7 is selected from (C1-6) alkyl, (C3-7) cycloalkyl, (C2-6) assorted alkyl, (C2-6) the assorted alkyl of ring; Or
(b) compound of general formula III
Figure A0281004100041
Wherein
X is selected from NR1, O, S;
Y1 and Y2 are independently selected from O, S;
Z is selected from NR2, O, S;
M is 0 or 1;
A is selected from direct key, (C1-6) alkyl, (C1-6) alkenyl, (C1-6) haloalkyl or contains (C1-6) assorted alkyl that is selected from the heteroatom group of N, O, S, SO, SO2 or contains two heteroatom groups that are selected from N, O, S, SO, SO2 and opened by at least two carbon atoms separate;
R1 is selected from H, (C1-3) alkyl, haloalkyl;
R2 is selected from H, alkyl, alkylhalide group;
R3 and R6 are independently selected from H, halogen (preferred F), alkyl, alkylhalide group, alkoxyalkyl, assorted alkyl, cycloalkyl, aryl, alkyl-cycloalkyl, alkyl-Heterocyclylalkyl, assorted alkyl-cycloalkyl, assorted alkyl-Heterocyclylalkyl, cycloalkyl-alkyl, cycloalkyl-assorted alkyl, Heterocyclylalkyl-alkyl, Heterocyclylalkyl-assorted alkyl, alkaryl, assorted alkyl-aryl, heteroaryl, miscellaneous alkyl aryl, assorted alkyl-heteroaryl, aralkyl, aryl-assorted alkyl, heteroaryl-alkyl, heteroaryl-assorted alkyl, two aryl, aryl-heteroaryl, heteroaryl-aryl, two heteroaryls contain the cycloalkyl or the Heterocyclylalkyl of 3 to 7 annular atomses, alkyl wherein, assorted alkyl, aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl can replace by optionally selected one or more groups from following group, and described group is selected from hydroxyl, alkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, halogen, alkylhalide group, hydroxyalkyl, alkoxyl group, alkoxyalkyl, halogen alkoxyl group, halo alkoxy alkyl, carboxyl, carboxyalkyl, alkyl carboxyl, amino, N-alkylamino, N, N-dialkyl amido, alkylamino, alkyl (N-alkyl) amino, alkyl (N, N-dialkyl group) amino, amido, N-alkyl amido, N, N-dialkyl group amido, alkyl amido, alkyl (N-alkyl) amido, alkyl (N, N-dialkyl group) amido, alkyl carbamate, alkyl urea, mercaptan, sulfone, sulfonamino (sulfonamido), alkyl sulfonyl amino, Arenesulfonyl amino, sulfonamido, alkylhalide group sulfone, alkyl sulfide, aryl sulphur, the alkyl sulfone, aryl sulfone, amino sulfone, N-alkylamino sulfone, N, N-dialkyl amido sulfone, alkylamino sulfone, the arylamino sulfone, cyano group, alkyl cyano group, guanidine radicals, N-cyano group-guanidine radicals, the sulphur guanidine radicals, amidino groups, N-aminosulfonyl-amidino groups, nitro, the alkyl nitro, 2-nitro-ethylidene-1,1-diamines;
R4 is selected from H, alkyl, hydroxyalkyl, alkylhalide group, alkoxyalkyl, halogen alkoxyl group, aminoalkyl group, acyl aminoalkyl, sulfane base;
R5 contains one, two or three each have the monocycle of the ring structure of 3 to 7 annular atomses, two ring or three cyclic groups, they are independently selected from cycloalkyl, aryl, Heterocyclylalkyl or heteroaryl, wherein each ring structure is optional is independently replaced by one or more substituting groups, these substituting groups are independently selected from halogen, thiolo, sulfane base, hydroxyl, alkyl-carbonyl, halogen alkoxyl group, amino, N-alkylamino, N, the N-dialkyl amido, cyano group, nitro, alkyl, alkylhalide group, alkoxyl group, the alkyl sulfone, amino-alkyl sulfinyl, alkylhalide group sulfone, alkyl amido, alkyl carbamate, alkyl urea, carbonyl, carboxyl, wherein the alkyl itself in any substituting group can optionally be replaced by one or more substituting groups, these substituting groups are independently selected from halogen, hydroxyl, amino, the N-alkylamino, N, N-dialkyl amido, alkyl sulfonyl amino, alkyl carboxyl amino, cyano group, nitro, mercaptan, alkyl sulfhydryl, alkyl sulfono, alkylamino sulfono, the alkyl carboxylic acid ester, amido, the N-alkyl amido, N, N-dialkyl group amido, alkyl carbamate, alkyl urea, alkoxyl group, halogen alkoxyl group, carbonyl, carboxyl;
When R5 is two rings or during three cyclic groups, each ring structure by direct key, by-O-, by-S-, by-NH-, by (C1-6) alkyl, by (C1-6) haloalkyl, by (C1-6) mix alkyl, by (C1-6) alkenyl, by (C1-6) alkynyl, by sulfone, be connected with the adjacent ring structure or condense with the adjacent ring structure by carboxyl (C1-6) alkyl;
R2 and R4 can optionally be connected to form and comprise can connecting into up to the ring of 7 annular atomses or R3 and R6 and contain the ring that reaches 7 annular atomses.
7. treat the disease of metalloprotease mediation or the method for illness for one kind, comprise the step of warm-blooded animal being treated hydrolyzable ester in the inhibitors of metalloproteinase compound of significant quantity or its pharmaceutically acceptable salt or its body, wherein this inhibitors of metalloproteinase compound is that any one is described for claim 1 to 6.
8. hydrolyzable ester is used for the treatment of by the purposes in the medicine of the disease of one or more metalloprotease mediations or illness in preparation in an inhibitors of metalloproteinase compound or its pharmaceutically acceptable salt or its body, and wherein this inhibitors of metalloproteinase compound is that any one is described for claim 1 to 6.
9. one kind is used for the treatment of by the disease of one or more metalloprotease mediations or the pharmaceutical composition of illness, it comprises hydrolyzable ester and medicine acceptable carrier in inhibitors of metalloproteinase compound or its pharmaceutically acceptable salt or its body, and wherein this inhibitors of metalloproteinase compound is that any one is described for claim 1 to 6.
10. the disease of metalloprotease mediation or the methods of treatment of illness, this method comprises the pharmaceutical composition of warm-blooded animal being treated significant quantity, said composition comprises hydrolyzable ester and medicine acceptable carrier in inhibitors of metalloproteinase compound or its pharmaceutically acceptable salt or its body, and wherein this inhibitors of metalloproteinase compound is that any one is described for claim 1 to 6.
CNA028100417A 2001-03-15 2002-03-13 Metalloproteinase inhibitors Pending CN1509275A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
SE01009034 2001-03-15
SE0100902A SE0100902D0 (en) 2001-03-15 2001-03-15 Compounds
SE01009026 2001-03-15
SE0100903A SE0100903D0 (en) 2001-03-15 2001-03-15 Compounds

Publications (1)

Publication Number Publication Date
CN1509275A true CN1509275A (en) 2004-06-30

Family

ID=26655413

Family Applications (1)

Application Number Title Priority Date Filing Date
CNA028100417A Pending CN1509275A (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors

Country Status (18)

Country Link
US (1) US20040147573A1 (en)
EP (1) EP1370536A1 (en)
JP (1) JP2004527511A (en)
KR (1) KR20030082990A (en)
CN (1) CN1509275A (en)
BR (1) BR0208105A (en)
CA (1) CA2440632A1 (en)
CZ (1) CZ20032502A3 (en)
EE (1) EE200300439A (en)
HU (1) HUP0400206A3 (en)
IL (1) IL157570A0 (en)
IS (1) IS6944A (en)
MX (1) MXPA03008180A (en)
NO (1) NO20034025L (en)
PL (1) PL364714A1 (en)
RU (1) RU2003127732A (en)
SK (1) SK10932003A3 (en)
WO (1) WO2002074750A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101080403B (en) * 2004-12-17 2010-09-08 阿斯利康(瑞典)有限公司 Novel hydantoin derivatives as metalloproteinase inhibitors

Families Citing this family (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE0100902D0 (en) * 2001-03-15 2001-03-15 Astrazeneca Ab Compounds
SE0100903D0 (en) * 2001-03-15 2001-03-15 Astrazeneca Ab Compounds
WO2002096426A1 (en) 2001-05-25 2002-12-05 Bristol-Myers Squibb Company Hydantion derivatives as inhibitors of matrix metalloproteinases
SE0103710D0 (en) * 2001-11-07 2001-11-07 Astrazeneca Ab Compounds
US20050119251A1 (en) * 2001-12-21 2005-06-02 Jian-Min Fu Nicotinamide derivatives and their use as therapeutic agents
WO2003106689A1 (en) * 2002-06-05 2003-12-24 鐘淵化学工業株式会社 PROCESS FOR PRODUCING OPTICALLY ACTIVE α-METHYLCYSTEINE DERIVATIVE
SE0202539D0 (en) 2002-08-27 2002-08-27 Astrazeneca Ab Compounds
SE0202692D0 (en) * 2002-09-11 2002-09-11 Astrazeneca Ab Compounds
SE0202693D0 (en) * 2002-09-11 2002-09-11 Astrazeneca Ab Compounds
GB0221250D0 (en) * 2002-09-13 2002-10-23 Astrazeneca Ab Compounds
GB0221246D0 (en) * 2002-09-13 2002-10-23 Astrazeneca Ab Compounds
WO2005016910A1 (en) * 2003-08-18 2005-02-24 Sankio Chemical Co., Ltd. Pyridyltetrahydropyridines, pyridylpiperidines, and process for the production of both
WO2005090316A1 (en) * 2004-03-12 2005-09-29 Wyeth HYDANTOINS HAVING RNase MODULATORY ACTIVITY
SE0401763D0 (en) * 2004-07-05 2004-07-05 Astrazeneca Ab Compounds
SE0401762D0 (en) * 2004-07-05 2004-07-05 Astrazeneca Ab Novel compounds
US7648992B2 (en) 2004-07-05 2010-01-19 Astrazeneca Ab Hydantoin derivatives for the treatment of obstructive airway diseases
CN101018782A (en) 2004-07-16 2007-08-15 先灵公司 Hydantoin compound for the treatment of inflammatory disorders
US7488745B2 (en) 2004-07-16 2009-02-10 Schering Corporation Compounds for the treatment of inflammatory disorders
US7504424B2 (en) 2004-07-16 2009-03-17 Schering Corporation Compounds for the treatment of inflammatory disorders
CN101084207A (en) * 2004-09-20 2007-12-05 泽农医药公司 Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors
EP1807085B1 (en) 2004-09-20 2013-08-21 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors
US7829712B2 (en) * 2004-09-20 2010-11-09 Xenon Pharmaceuticals Inc. Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase
AU2005329423A1 (en) * 2004-09-20 2006-09-28 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US7547698B2 (en) * 2004-09-20 2009-06-16 Xenon Pharmaceuticals Inc. Bicyclic heterocyclic derivatives and their use as inhibitors of stearoyl-coadesaturase (SCD)
JP5094398B2 (en) * 2004-09-20 2012-12-12 ゼノン・ファーマシューティカルズ・インコーポレイテッド Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturases
EP2289510A1 (en) * 2004-09-20 2011-03-02 Xenon Pharmaceuticals Inc. Heterocyclic derivatives for the treatment of diseases mediated by stearoyl-coa desaturase enzymes
DE602005025924D1 (en) * 2004-09-20 2011-02-24 Xenon Pharmaceuticals Inc Royl-coa-desaturase
MX2007003321A (en) * 2004-09-20 2007-06-05 Xenon Pharmaceuticals Inc Heterocyclic derivatives and their use as therapeutic agents.
SE0403085D0 (en) * 2004-12-17 2004-12-17 Astrazeneca Ab Novel componds
CN101208089A (en) * 2005-06-03 2008-06-25 泽农医药公司 Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors
AR059037A1 (en) 2006-01-17 2008-03-12 Schering Corp COMPOUNDS FOR THE TREATMENT OF INFLAMMATORY DISORDERS
TW200800954A (en) * 2006-03-16 2008-01-01 Astrazeneca Ab Novel crystal modifications
TW200740769A (en) * 2006-03-16 2007-11-01 Astrazeneca Ab Novel process
TW200831488A (en) * 2006-11-29 2008-08-01 Astrazeneca Ab Novel compounds
WO2009007747A2 (en) * 2007-07-11 2009-01-15 Astrazeneca Ab Hydantoin derivatives used as mmp12 inhibitors
US8859529B2 (en) 2008-09-24 2014-10-14 Merck Sharp & Dohme Corp. Compounds for the treatment of inflammatory disorders
EP2346857B1 (en) 2008-09-24 2019-11-27 Merck Sharp & Dohme Corp. Compounds for the treatment of inflammatory disorders
EP2356111A1 (en) 2008-11-10 2011-08-17 Schering Corporation Compounds for the treatment of inflammatory disorders
WO2010054278A2 (en) 2008-11-10 2010-05-14 Schering Corporation Compounds for the treatment of inflammatory disorders
HU1000676D0 (en) * 2010-12-17 2011-02-28 Pharmahungary 2000 Kft Inhibitors of matrix metalloproteinase, pharmaceutical compositions thereof and use of them for preventing and treating diseases where the activation of mmp is involved
CA2914178C (en) 2013-01-07 2023-06-13 University Of Southern California Deoxyuridine triphosphatase inhibitors
RU2668072C2 (en) * 2013-06-07 2018-09-27 Какен Фармасьютикал Ко., Лтд. (+)-5-(3,4-difluorophenyl)-5-[(3-methyl-2-oxopyridin-1(2h)-yl)methyl]imidazolidine-2,4-dione and drug containing same
WO2017006283A1 (en) 2015-07-08 2017-01-12 Cv6 Therapeutics (Ni) Limited Deoxyuridine triphosphatase inhibitors containing cyclopropano linkage
US10577321B2 (en) 2015-07-08 2020-03-03 University Of Southern California Deoxyuridine triphosphatase inhibitors
US10570100B2 (en) 2015-07-08 2020-02-25 University Of Southern California Deoxyuridine triphosphatase inhibitors containing amino sulfonyl linkage
EP3319939A1 (en) 2015-07-08 2018-05-16 CV6 Therapeutics (NI) Limited Hydantoin containing deoxyuridine triphosphatase inhibitors
US10858344B2 (en) 2016-11-23 2020-12-08 Cv6 Therapeutics (Ni) Limited Hydantoin containing deoxyuridine triphosphatase inhibitors
US11168059B2 (en) 2016-11-23 2021-11-09 Cv6 Therapeutics (Ni) Limited Amino sulfonyl compounds
WO2018098208A1 (en) 2016-11-23 2018-05-31 Cv6 Therapeutics (Ni) Limited Nitrogen ring linked deoxyuridine triphosphatase inhibitors
US11174271B2 (en) 2016-11-23 2021-11-16 Cv6 Therapeutics (Ni) Limited 6-membered uracil isosteres
US11014924B2 (en) 2016-11-23 2021-05-25 Cv6 Therapeutics (Ni) Limited Hydantoin containing deoxyuridine triphosphatase inhibitors
WO2018128720A1 (en) 2017-01-05 2018-07-12 Cv6 Therapeutics (Ni) Limited Uracil containing compounds
AR110963A1 (en) 2017-02-07 2019-05-22 Dae Woong Pharma HETEROCYCLIC COMPOUNDS, THEIR METHOD OF PREPARATION AND PHARMACEUTICAL COMPOSITION THAT UNDERSTANDS
AU2019270975B2 (en) * 2018-05-15 2023-12-14 Foresee Pharmaceuticals Co., Ltd Matrix metalloproteinase (MMP) inhibitors and methods of use thereof

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3529019A (en) * 1968-04-23 1970-09-15 Colgate Palmolive Co Alkylaryloxy alanines
CS151744B1 (en) * 1971-01-19 1973-11-19
US3849574A (en) * 1971-05-24 1974-11-19 Colgate Palmolive Co Alpha-substituted-beta-arylthioalkyl amino-acids,for increasing heart rate
US5268291A (en) * 1983-01-19 1993-12-07 Genentech, Inc. Human t-PA production using vectors coding for DHFR protein
EP0640594A1 (en) * 1993-08-23 1995-03-01 Fujirebio Inc. Hydantoin derivative as metalloprotease inhibitor
PL337854A1 (en) * 1997-07-31 2000-09-11 Abbott Lab Inverse hydroxamines as inhibitors of intercellular substance metaloproteinases
ATE231837T1 (en) * 1997-11-12 2003-02-15 Darwin Discovery Ltd HYDROXAMIC ACID AND CARBOXIC ACID DERIVATIVES WITH MMP AND TNF INHIBITING EFFECTS
WO2000040577A1 (en) * 1998-12-31 2000-07-13 Aventis Pharmaceuticals Inc. 1-carboxymethyl-2-oxo-azepan derivatives useful as selective inhibitors of mmp-12
US6294694B1 (en) * 1999-06-04 2001-09-25 Wisconsin Alumni Research Foundation Matrix metalloproteinase inhibitors and method of using same
GB9916562D0 (en) * 1999-07-14 1999-09-15 Pharmacia & Upjohn Spa 3-Arylsulfonyl-2-(substituted-methyl) propanoic acid derivatives as matrix metalloproteinase inhibitora

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101080403B (en) * 2004-12-17 2010-09-08 阿斯利康(瑞典)有限公司 Novel hydantoin derivatives as metalloproteinase inhibitors

Also Published As

Publication number Publication date
EP1370536A1 (en) 2003-12-17
CA2440632A1 (en) 2002-09-26
IL157570A0 (en) 2004-03-28
NO20034025D0 (en) 2003-09-11
BR0208105A (en) 2004-03-09
JP2004527511A (en) 2004-09-09
KR20030082990A (en) 2003-10-23
RU2003127732A (en) 2005-03-20
SK10932003A3 (en) 2004-04-06
CZ20032502A3 (en) 2004-01-14
EE200300439A (en) 2003-12-15
MXPA03008180A (en) 2003-12-12
NO20034025L (en) 2003-11-13
US20040147573A1 (en) 2004-07-29
IS6944A (en) 2003-09-10
WO2002074750A1 (en) 2002-09-26
HUP0400206A2 (en) 2004-08-30
HUP0400206A3 (en) 2004-10-28
PL364714A1 (en) 2004-12-13

Similar Documents

Publication Publication Date Title
CN1509275A (en) Metalloproteinase inhibitors
CN1269804C (en) Metalloproteinase inhibitors
CN1183119C (en) Arylpiperzines as metalloproteinase inhibiting agents (MMP) and their use
CN1509274A (en) Metallo proteinase inhibitors
CN1913886A (en) Heterocyclic aspartyl protease inhibitors
AU2002237626A1 (en) Metalloproteinase inhibitors
JP4256095B2 (en) Piperidine- and piperazine-substituted N-hydroxyformamides as inhibitors of metalloproteinases
AU2002237629A1 (en) Metalloproteinase inhibitors

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication